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Abstract | Mitochondria are increasingly recognized as key players in genetic and acquired
renaldiseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by
tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described.
Forexample, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G
mutation are important causes of focal segmental glomerulosclerosis in children and in adults,
respectively. Although they sometimes present with isolated renal findings, mitochondrialdiseases
are frequently associated with symptoms related to central nervous system and neuromuscular
involvement. They can result from mutations in nuclear genes that are inherited according to
classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according
to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves
clinical characterization of patients in combination with biochemical and genetic analyses.
Inparticular, prompt diagnosis of CoQ10 biosynthesis defectsisimperative because of their
potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes
tothe physiopathology of tissue injury, whereasmitochondrial biogenesis has an important role in
the recovery of renal function. Potential therapies that target mitochondrial dysfunction
orpromote mitochondrial regeneration are being developed to limit renal damage during AKI
andpromote repair of injured tissue.
Division of Nephrology and
Dialysis, Ospedale Pediatrico
Bambino GesIRCCS, Piazza
SantOnofrio 4, 00165Rome,
Italy.
2
Pediatric Nephrology and
Dialysis Unit, Department
ofClinical Sciences and
Community Health, University
of Milan, Fondazione IRCCS
Ca Granda Ospedale
Maggiore Policlinico, Viadella
Commenda 9, Milano, Italy.
3
Division of Nephrology and
Center for Vascular Biology
Research, Beth Israel
Deaconess Medical
Centerand Harvard Medical
School,330 Brookline
Avenue,Boston,
Massachusetts02215, USA.
4
Clinical Genetics Unit,
Department of Woman and
Child Health, University of
Padova, Via Giustiniani 3,
35128, Padova, Italy.
Correspondence to F.E.
francesco.emma@opbg.net
1
doi:10.1038/nrneph.2015.214
Published online 25 Jan 2016
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Key points
Healthy mitochondria are essential for normal kidney function; mitochondrial
cytopathies can result in renal disease and mitochondrial damage has a role in the
pathophysiology of acute kidney injury (AKI)
Although mitochondrial diseases are characterized by maternal inheritance, many
mitochondrial disorders are caused by mutations in nuclear genes and are inherited
according to classic Mendelian rules
Most mitochondrial diseases with kidney involvement cause tubular defects;
however,mutations in the coenzymeQ10 biosynthesis pathway and the mtDNA 3243
A>G mutation primarily cause glomerular disease
Diagnosis of genetic mitochondrial disorders increasingly relies on new sequencing
techniques, but thorough biochemical and clinical characterization of patients is
essential to guide these analyses
In AKI, mitochondrial dysfunction precedes and participates in the physiopathology
of tissue damage; mitochondrial biogenesis might represent a crucial step in the
recovery phase
Potential therapies that target mitochondrial dynamics, mitophagy and/or
mitochondrial biogenesis might limit renal damage during AKI and promote recovery
of kidney function
Description
Maternal inheritance
Both genders might be affected by mtDNA mutations, but only females transmit mutations
totheir children
Heteroplasmy
Wild-type and mutant mtDNA molecules can coexist in different proportions within cells of
thesame tissue or in different tissues of the same individual
Threshold effect
A mutation must affect a critical proportion (usually >70%) of the total mtDNA molecules
within a cell or tissue to cause a biochemical effect resulting in a clinical phenotype
Random drift
Mutant and wild-type mtDNA molecules segregate randomly in daughter cells during each
celldivision
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Mitochondrial matrix
Carbohydrates
Lipids
Pyruvate
AcetylCoA
CO2
NADH
e-
H+
H+
H+
Krebs
cycle
H+
ADP
Complex I
Complex III
CoQ
Complex II
CoQ
eComplex IV
Cytochrome c
H+
ATP
O2
H+
H+ H2O
Complex V
H+
Figure 1 | Mitochondrial energy metabolism and the respiratory chain. Acetyl-coenzyme A (Acetyl-CoA) is the terminal
Nature
| Nephrology
product of carbohydrate and lipid metabolism, and is oxidized through the reactions of the Krebs
cycleReviews
to produce
CO2.
Thehigh energy electrons (e ) produced by these reactions enter the respiratory chain and eventually reduce molecular
oxygen (02) to form water (H20). The energy released by this process is used to pump protons (H+) acrossthe mitochondrial
inner membrane and generate the electrochemical gradient that enables complex V to synthesize ATP. The red ovals
represent mitochondrial DNA-encoded subunits of the respiratory chain complexes. CoQ, coenzyme Q.
REVIEWS
RNA polymerase
Transcription factors
RNA maturation and stabilization
Aminoacyl-tRNA
synthetases
Elongation or
termination factors
Ribosomal proteins
DNA polymerase
Helicases
Proteins involved in
nucleotide metabolism
rRNA
mtDNA
tRNA
Mitochondrial
protein synthesis
mtDNA replication
and maintenance
mRNA
CoQ
biosynthetic
complex
Complex III
Complex II
Complex IV
CoQ
Cytochrome c
Complex I
Structural components
Complex V
Assembly factors
nDNA
Figure 2 | Interplay of mitochondrial and nuclear genes in the biogenesis of the respiratory chain. Mitochondrial (mt)
Nature Reviews | Nephrology
DNA encodes 13 structural subunits of the respiratory chain complexes (red ovals) as well as two ribosomal (r)RNAs and
22transfer (t)RNAs that are required for mitochondrial protein synthesis. Nuclear (n)DNA encodes all the other structural
subunits of the respiratory chain complexes, cytochromec, assembly factors, the enzymes required for coenzyme Q (CoQ)
biosynthesis and proteins involved in mtDNA replication and maintenance and in mitochondrial protein synthesis.
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Table 2 | Genetic defects that impair mitochondrial function
Defect
mtDNA
Mitochondrial
protein synthesis
Point mutations or gross rearrangements in mtDNA usually impair mitochondrial protein synthesis as a whole, resulting in
combined defects of several respiratory chain complexes10; complex II is spared, as only nuclear genes encode this complex
Many point mutations affect genes that encode tRNAs or rRNAs
The most frequent gross rearrangement is the recurrent 4,977 base pair common deletion142
The renal phenotype is usually tubulopathy; glomerular defects are associated with the mtDNA 3243 A>G mutation
Structural subunits
Mutations in mtDNA-encoded structural subunits usually cause defects in individual respiratory chain complexes
nDNA
Assembly factors
Assembly factors are not part of the respiratory chain, but are necessary for its biogenesis; mutations in genes that encode
assembly factors are usually referred to as indirect hits
Some assembly factors are required for specific steps in the biogenesis of individual complexes (for example COX10 encodes
a farnesyltransferase that is involved in the biosynthesis of the heme group of complex IV143), whereas others have shared
functions and their mutations consequently affect multiple complexes, often including complex II (for example, mutations
inLYRM4, which is required for the synthesis of ironsulphur clusters, impair the activities of complexes I, II and III144)
Electron carriers
Mutations in genes that are required for CoQ10 biosynthesis cause primary CoQ10 deficiency
Secondary CoQ10 deficiency is associated with mutations in nDNA genes that are not directly involved in CoQ10 biosynthesis,
such as APTX and ETFDH, as well as with several mtDNA defects89; therefore, a reduction in CoQ10 levels does not necessarily
indicate a mutation in a COQ gene
Secondary forms of CoQ10 deficiency are probably much more frequent than primary forms
Mutations in cytochromec are transmitted as autosomal dominant traits and associated with familial thrombocytopenia;
thedisease pathogenesis results from deregulation of apoptosis rather than the bioenergetic defect
Mitochondrial
dynamics
The most common defects in genes that control mitochondrial dynamics involve the profusion proteins OPA1 and mitofusin2
In addition to promoting mitochondrial fusion, OPA1 is essential for the control of cristae remodelling and the formation of
supercomplexes145, which increase the efficiency of oxidative phosphorylation
Mitofusin2 tethers mitochondria to the endoplasmic reticulum; this process is probably important for calcium metabolism146
Mitochondrial
protein synthesis
Genes that are involved in mitochondrial protein synthesis include those that encode aminoacyltRNA synthases,
mitochondrial ribosomal proteins, elongation factors, proteins that are involved in the maturation of mRNAs and tRNAs,
andother components of the translation machinery10
Mutations in these genes typically result in combined defects that spare complex II
mtDNA
maintenance
Mutations in genes that encode proteins involved in mtDNA replication or nucleotide metabolism cause secondary mtDNA
defects, including depletion (reduction in copy number), multiple deletions (resulting in the tissue-specific presence of
mtDNA species with various types of gross deletions) and specific point mutations147
Defects in mtDNA maintenance are usually associated with combined deficiencies
Some defects alter the lipid milieu of the mitochondrial inner membrane and indirectly impair oxidative phosphorylation15;
forexample, TAZ mutations result in Barth syndrome, which is characterized by abnormal cardiolipin metabolism
OPA1 and mitofusin2 are also required for mtDNA maintenance and their deficiencies cause mtDNA depletion by
unclearmechanisms145
Structural subunits
Nuclear gene defects might directly involve structural subunits of individual complexes, most commonly complexI
CoQ10, coenzyme Q10; mRNA, messenger RNA; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; OPA1, optic atrophy 1 (also known as dynamin-like 120 kDa
protein, mitochondrial); tRNA, transfer RNA.
resulting in impaired mitochondrial oxidative phosphorylation with a dominant-negative effect. The latter finding is further substantiated by the absence of
Fanconi syndrome in Ehhadh-knockoutmice60.
Glomerular diseases
Podocytes are highly differentiated cells with limited
replicative capacity. They are a major component of the
glomerular filtration barrier, support the other capillary
components in counteracting endocapillary pressure,
synthesize major cytoskeletal proteins and extracellular
matrix components, and have several immunological
roles61. To maintain all of these functions, podocytes are
particularly dependent on energy and are rich in mito
chondria. Impairment of oxidative phosphorylation
inpodocytes results in excessive generation of ROS
andin functional and structural alterations, resulting in
disruption of the glomerular filtration barrier, protein
uria and ultimately the development of glomerular sclerotic lesions62,63. Podocyte mitochondrial dysfunctions
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Table 3 | Nuclear gene defects that affect respiratory chain biogenesis
Category
Gene
Renal phenotype
Structural subunits
Refs
NA
NA
SRNS
73
SRNS
72
COQ2
SRNS
71
COQ6
SRNS
68
ADCK4
SRNS
69
COQ9
Tubulopathy
44
COX10
Tubulopathy
148
SURF1
Tubulopathy*
149
BCS1L
Tubulopathy
150
UQCC2
Tubulopathy
151
TMEM70
Tubulopathy*
152
MRPS22
Tubulopathy
153
YARS2
Tubulopathy
154
SARS2
Tubulopathy
155
RRM2B
Tubulopathy
156
TWINKLE
Tubulopathy
157
MPV17
Tubulopathy
158
SUCLA2
Tubulopathy*
159
DGUOK
Tubulopathy*
160
Lipid milieu
NA
NA
Mitochondrial dynamics
NA
NA
Assembly factors
mtDNA translation
mtDNA maintenance
CoQ, coenzyme Q; mtDNA, mitochondrial DNA; NA, not applicable; SRNS, steroid-resistant
nephrotic syndrome. *Occasional manifestation.
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from two unrelatedfamilies72,80. The first family, with
three affected siblings, was originally described in
2006 (REF.81). Allthree children presented with progressive encephalopathy and SRNS; two children
underwent successful renal transplantation at the ages
of 8years and 9years, whereas the third child died at
8years of age as a consequence of rapid neurological
deterioration. Treatment with oral CoQ10 (5mg/kg per
day) improved the neurologic symptoms in the surviving children over 3years of followup. In the second
family, the patient presented at 3months of age with
seizures and hypotonia. He subsequently developed
cortical blindness and nephrotic syndrome and died
at 8months of age because of severe refractory focal
status epilepticus72. His brain MRI was compatible
with Leigh syndrome. From 3months of age, this child
was treated with oral CoQ10 (50mg per day) with no
apparent clinical improvement. The reasons for this
lack of response are unclear, but the treatment might
have been started too late, when neurological and renal
lesions could no longer regress. Two patients with
PDSS1 mutations have also been described: the first
showed no renal abnormalities82 whereas the second
presented with nephroticsyndrome73.
A mouse model (kd/kd) harbouring a spontaneous
homozygous missense mutation in Pdss2 recapitulates
the human renal phenotype and does not show major
extra-renal defects83. In this model, CoQ10 supplementation is effective in preventing the onset of renal disease84. Interestingly, treatment with the antioxidant and
hypolipidemic compound probucol is also effective in
preventing renal lesions in these mice85. Whether this
beneficial effect is related to the antioxidant properties
of probucol or whether the drug stimulates CoQ9 bio
synthesis in these animals is unclear. No clinical data
on probucol are available, but other antioxidants, such
as idebenone (a soluble analogue of CoQ10) do not
rescue defects that result in a reduction in the activity of complex II+III86 and seem to be ineffective at
ameliorating symptoms in animal models80. The role
of ROS in the pathogenesis of glomerulopathy in the
kd/kd mouse model is supported by the observation
that CoQ9 deficiency is ubiquitous in these animals, but
a significant increase in ROS production is present only
in the kidneys, where tissue damage occurs87.
COQ6. COQ6 encodes a mono-oxygenase, which
catalyses the C5 hydroxylation step of the quinone
ring. Mutations in this gene have been described in
11patients from five families 68. All of the affected
children presented with SRNS and sensorineural deafness, generally at older ages than those reported for
patients with COQ2 mutations. Proteinuria was diagnosed between 0.2years and 6years of age (median
1.2years) and renalfunction deteriorated rapidly to
reach end-stage renal disease (ESRD) between 0.4years
and 9years of age (median 1.7years). Five children
died at a median age of 5years. The most frequent
renal histological picture (seen in seven patients) was
FSGS; diffuse mesangial sclerosis was diagnosed in one
biopsy sample. Facial dysmorphism and neurological
Common manifestation
Endocrine system
Diabetes mellitus
Hypoparathyroidism
Gastrointestinal
tract
Intestinal dysmotility
Pseudo-obstruction
Malabsorption
Heart
Haematologic
system
Sideroblastic anaemia
Thrombocytopenia
Neutropenia
Liver
Liver failure
Nervous system
Psychomotor retardation
and/orregression
Dementia
Seizures
Myoclonus
Migrane
Ataxia
Spasticity
Dystonia
Stroke-like episodes
Leukoencephalopathy
Peripheral neuropathy
Sensory system
Deafness
Blindness
Optic nerve atrophy
Retinitis pigmentosa
Cataracts
Progressive external
ophthalmoplegia
Skeletal muscles
Muscle weakness
Exercise intolerance
Myoglobinuria
impairment, including seizures, white matter abnormalities and ataxia, were also reported68. Notably the
uniformity of the phenot ype, and in particular the
renal involvement, could reflect selection bias as all
of the patients were identified from a SRNS cohort.
A yeast complementation study that tested all of the
mutated COQ6 alleles reported to date, showed that the
defect could be rescued by vanillic acid or dihydroxy
benzoic acid (DHB)19. These nontoxic analogues of the
ring precursor of CoQ10 are able to bypass the enzymatic defect. DHB has also been shown to be effective
in fibroblasts from patients with COQ7 mutations88.
ADCK4. ADCK4 is the human orthologue of the yeast
COQ8 gene (L. Salviati, unpublished data), which
encodes an atypical kinase involved in the regulation of
CoQ10 biosynthesis. In yeast, overexpression of ADCK4
stabilizes the CoQ multienzyme biosynthetic complex, even in the absence of any of its components89.
Mutations in ADCK4 account for the highest number
of patients with renal disease secondary to CoQ10 biosynthesis defects reported to date: 38 patients from
18families have been retrospectively described69,90.
These patients typically presented with proteinuria
and SRNS and most had a renal histological picture
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a
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Diagnosis of oxidative phosphorylation defects
Analysis of lactate levels
The diagnosis of defects in oxidative phosphory
lation is a complex task that requires a combination
of approaches10. As a functional respiratory chain is
required for the oxidation of lactate (the final productof
glycolysis) to carbon dioxide and water, the presence of
increased lactate levels in serum or cerebrospinal fluid
is an important finding. Such analyses can be integrated
with magnetic resonance spectroscopy, which enables
estimation of lactate levels in the brain98. These levels
often fluctuate, however, and might be normal even in
the presence of severe defects in oxidative phosphory
lation99. The lactate-topyruvate ratio helps distinguish
between oxidative phosphorylation disorders and
other defects such as pyruvate dehydrogenase deficiency. Analysis of urinary organic acids might detect
lacticaciduria and other abnormalities, such as dicarboxylic aciduria, which is a frequent, albeit nonspecific
finding in patients with defects in oxidative phosphory
lation24. Patients with mitochondrial renal disease often
do not have constant hyperlactacidemia but might have
elevated urinary lactate excretion. In addition, levels
of fibroblast growth factor21 are increased in patients
who have mitochondrial disorders with significant
muscleinvolvement 100.
Neuroimaging
Neuroimaging often provides important clues to aid
diagnosis. Focal lesions in deep grey matter structures,
such as the putamen and basal ganglia, are among
the most common findings, especially in paediatric
patients101,102. Leigh syndrome, which is characterized by
focal, bilateral, symmetric lesions involving basal ganglia
and the periaqueductal grey matter, represents the effects
of severe deficiencies in energy production inthe central
nervous system in infancy 103. Older patients might present with stroke-like lesions in non-vascular territories,
especially in the parieto-occipital region. These lesions
are typical of MELAS syndrome101, but are also seen
in other defects, including CoQ10 deficiencies74. Lessspecific findings include cortical and cerebellar atrophy,
as well as various white matter abnormalities.
Analysis of biopsy samples
Muscle biopsy is still considered the gold standard
for diagnosis of oxidative phosphorylation defects10.
Morphological analyses coupled with histochemical
staining enables the detection of COX-deficient fibres
and mitochondrial proliferation104. A uniform pattern
points to a nDNA defect, whereas a mosaic distribution (owing to heteroplasmy) is suggestive of a mtDNA
abnormality, which can occur as a result of a mutation
in mtDNA or as a secondary effect of a mutation in a
nuclear mtDNA maintenance gene. Oil-Red staining
might detect lipid accumulation, which is often observed
in CoQ10 deficiencies105.
Spectrophotometric measurements of enzymatic
activities might distinguish between defects involving individual complexes and combined deficiencies.
Analysis of the combined activity of complexes II and III,
Next-generation sequencing
Next-generation sequencing approaches are revolutionizing the molecular diagnosis of mitochondrial dis
orders. The entire mtDNA can now be sequenced rapidly
at low cost108. In patients with renal involvement, urinary
sediment cells could be the optimal material for DNA
extraction109. Likewise, in cases of nuclear defects, large
gene panels or the entire exome can now be analysed19.
In the past few years, numerous defects have been characterized at the molecular level using these techniques.
Nonetheless, detailed phenotypic characterization of
patients remains necessary to restrict the data analysis,
which is time consuming and complicated.
Screening for CoQ 10 deficiency. As timely diagnosis is crucial for the success of therapy, the possibility
of CoQ10 deficiency should always be considered in
patients with SRNS, particularly infants. No pathog
nomonic clinical features exist, but SRNS in association
with neuromuscular symptoms or deafness should raise
the suspicion of CoQ10 deficiency. Many patients, however, present with SRNS without extrarenal involvement
at diagnosis. Moreover, although patients usually present in infancy or early childhood, onset of symptoms
might occur later in life. The optimal diagnostic strategy for CoQ10 deficiency is still debated110. Traditional
approaches require time and invasive procedures; such
delay is not of critical importance in most disorders of
oxidative phosphorylation, but might have dramatic consequences in the case of CoQ10 deficiencies. In principle,
all individuals with isolated SRNS should be screened for
CoQ10 deficiency, but performing a skin or muscle biopsy
is not always possible. With new technological advances
and cost reductions, screening using next-generation
sequencing and specific gene panels is becoming a valuable diagnostic approach. Even if only 1% of patients
with SRNS have CoQ10 deficiency 111, the benefits of preventing ESRD and probably also neurological deterior
ation in these patients outweighs the cost of genetic
screening, which is routinely performed in most cases.
Systematic electron microscopy of renal biopsy samples
could also enable rapid identification of many patients,
as abnormal mitochondrial proliferation in podocytes is
frequentlyobserved75.
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Mitochondrial dysfunction in acute kidney injury
As the renal tubules represent one of the most metabolically active epithelia in the human body, it is unsurprising that AKIwhether septic, ischaemic, or toxic
in origininvolves early pathological changes in the
mitochondria of the tubular epithelium112,113. These
changes include decreased mitochondrial abundance,
swelling of individual organelles, and disruption of
the otherwise tightly stacked cristae. The proximal
tubule is a primary site for mitochondrial disruption
in AKI, but changes in the thick ascending limb and
distal tubules have also been reported114. Evidence for
mitochondrial involvement in human AKI was shown
in early electron microscopy studies of specimens from
patients who had died from septic shock115. Subsequent
autopsy studies following sepsis and sequential biopsy
studies during controlled renal ischaemia (for example, for nephrectomy) revealed similar lesions in
mitochondria116,117.
Mitochondrial dysfunction in AKI typically accompanies ultrastructural pathology. For example, experimental cisplatin nephrotoxicity induces a decrease in
the activity and expression of cytochromec oxidase
in the proximal tubule, but not in the distal nephron
segments. This finding is consistent with the clinical observation that proximal tubular manifestations
dominate the presentation of platinum-induced renal
injury 118. Comparison of a toxic form of AKI, glycerol-
induced rhabdomyolysis, with post-ischaemic AKI
showed that both conditions result in widespread loss
of mitochondrial respiratory proteins from proximal
tubules119, whereas experimental sepsis leads to a profound decrease in the expression and activity of multiple
enzymatic components of the mitochondrial electron
transport chain112.
Injured mitochondria not only deprive the cell of
ATP, but are an important source of molecules that
amplify injury, precipitate cell death and induce inflammation (FIG.4). ROS released from damaged mitochondria contribute to the oxidative stress widely reported in
AKI. Structural disruption of mitochondria also releases
cytochromec, a trigger of apoptosis, as well as mtDNA,
which can serve as a proinflammatory danger signal120.
Ahighly orchestrated process of mitochondrial biogenesis, replication, and clearance via macroautophagy
enables healthy cells to avoid the dangers of mitochondrial injury. Conversely, growing evidence indicates that
mitochondria might be a compelling therapeutic target
in multiple forms ofAKI.
Fatty acids
Although comprehensive discussion of mitochondrial
energy metabolism in AKI is beyond the scope of this
Review, the roles of fatty acids and ROS need to be
highlighted. Fatty acids are the most efficient source of
mitochondrial ATP generation, but their intracellular
accumulation can result in lipotoxicity. Duringischaemia, a mismatch develops between ongoing hydrolysis
of membrane phospholipids and reduced clearance of
these fatty acids via reesterification and mitochondrial fatty acid oxidation. This imbalance leads to the
Mitochondrial dynamics
Ischaemic and toxic forms of AKI are characterized
by marked mitochondrial fragmentation. The fragmented mitochondria are potential sources of ROS,
cytochromec, mitochondrial DNA and other potentially
injurious molecules. Inhibition of mitochondrial fission
by genetically or pharmacologically blocking dynamin-
related protein 1 (Drp1) has been shown to protect cultured renal tubular cells from stress-induced apoptosis
and attenuate AKI following ischaemiareperfusion
or cisplatin exposure 113 . Experimental pigment
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Induction of PGC-1-
Formoterol
Rapamycin
Biogenesis
Mitophagy
Recovery
Cell death
Proximal
tubule cell
Citric acid
cycle substrates
Acute kidney injury
Nucleus
Complex
network of
healthy
mitochondria
Accumulation of
fatty acids
Weakened membrane
structure
Oxidative stress
Toxins
Inammation
Ischaemia
Mitochondrial swelling
and fragmentation
ATP production
ATP production
Disruption
of cristae
ROS
production
Release of
cytochrome c,
caspases and
mtDNA
Mitochondrial
targeted
antioxidants
Caspases
ROS
ATP
Cytochrome c
mtDNA
Figure 4 | Mitochondrial injury and recovery during acute kidney injury (AKI). Tubular epithelial cells in the proximal
tubule and outer medulla are heavily invested with mitochondria in order to generate the ATP necessary for solute
Nature
Reviews | Nephrology
transport. Diverse aetiologies of AKI injure the mitochondria, leading to organellar swelling and
fragmentation.
Injured
mitochondria, in turn, release an array of proinflammatory and injurious molecules, such as reactive oxygen species (ROS),
which, if unchecked, promote cell death. Experimental findings suggest that recovery from AKI might require the
clearance of injured mitochondria through mitophagy and the replenishment of mitochondrial mass through
mitochondrial biogenesis, a process mediated by the transcriptional coactivator peroxisome proliferator-activated
receptor co-activator 1 (PGC1). Examples of potential preventive and therapeutic strategies are highlighted in pink
boxes. mtDNA, mitochondrial DNA.
nephropathy can also be ameliorated by Drp1 inhibition132. Although complementary experiments with
gainoffunction mutations remain to be performed,
these findings suggest that altered mitochondrial
dynamics are a key feature of AKI and a potential therapeutic target. Consistent with this hypothesis, experimental evidence suggests that the NAD-dependent
protein deacetylase sirtuin 3 might attenuate cisplatin-
induced mitochondrial fragmentation and protect
against experimentalAKI133.
Mitophagy
Safe disposal of fragmented mitochondria via mitophagy
might protect stressed cells from death and ameliorate
AKI. Renal IRI has been shown to induce mitophagy
in renal tubules134, and mice that lack the autophagy
regulator Atg7 show increased sensitivity to cisplatin
nephrotoxicity 135. Drugs that induce mitophagy, such
as rapamycin, merit further exploration as therapeutic
strategies to enhance the clearance of injury-propagating
fragmented mitochondria and accelerate recovery
afterAKI.
Mitochondrial biogenesis
To maintain a steady pool of mitochondria, losses to
mitophagy must be replenished by the expansion of
mitochondrial mass. An array of nuclear transcription factors and coactivators are involved in mitochondrial biogenesis. The best studied coactivator is
peroxisome proliferator-activated receptor co-activator1 (PGC1), which is highly expressed in the
most metabolically active organs, including the heart,
kidney, brains, skeletal muscle and liver 136. In the kidney
PGC1 expression reflects the relative distribution of
mitochondria; the highest expression is in the cortex,
followed by the tubules with much lower levels in the
glomerulus112. In ischaemic and septic AKI, an initial
decrease in PGC1 expression is followed by a return
to normal levels as organ function recovers, suggesting a
role of thisco-activator in AKI recovery 112,119. Consistent
withthis hypothesis, specific knockout of Ppargc1a,
which encodes PGC1, from the proximal tubule
blunted renal recovery following experimental sepsis112.
Signals from innate inflammatory pathways might result
in downregulation of PGC1 duringinfection137,138.
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Data from gainoffunction experiments also suggest that targeting mitochondrial biogenesis might
attenuate renal injury and/or accelerate recovery from
AKI. In cultured proximal tubular cells, induction
of PGC1 after (but not before) oxidant exposure
accelerated recovery of mitochondrial function 139.
To identify pharmac ological stimulators of mitochondrial biogenesis, Jesinkey etal. screened a large
library of small molecules in model cellular systems.
One such compound, the adrenergic agonist formoterol, stimulated mitochondrial biogenesis, reduced
necrosis and improved kidney function in mice that
had been subjected to renal IRI140. Further studies are
required to determine whether PGC1 is required for
formoterol-dependent renoprotection, and to delineate
the underlying mechanisms. However, these findings
are promising because they suggest the translational
utility of unbiased cell-based drug screens targeting
mitochondrial processes to identify agents that might
aid recovery from establishedAKI.
Conclusions
Healthy mitochondria are essential for normal renal
health and mutations that directly or indirectly impair
mitochondrial function or assembly can cause renal
disease. The genetics of mitochondrial disorders is
complex and can follow various patterns of inheritance.
Although most patients with renal disease resulting
1. Andersson,S.G. etal. The genome sequence of
Rickettsia prowazekii and the origin of mitochondria.
Nature 396, 133140 (1998).
2. Frey,T.G. &Mannella,C.A. The internal structure
ofmitochondria. Trends Biochem. Sci. 25, 319324
(2000).
3. Anderson,S. etal. Sequence and organization of the
human mitochondrial genome. Nature 290, 457465
(1981).
4. Schon,E.A., DiMauro,S. &Hirano,M. Human
mitochondrial DNA: roles of inherited and somatic
mutations. Nat. Rev. Genet. 13, 878890 (2012).
5. Opalinska,M. &Meisinger,C. Metabolic control
viathemitochondrial protein import machinery.
Curr.Opin. Cell Biol. 33, 4248 (2015).
6. Dimmer,K.S. &Scorrano,L. (De)constructing
mitochondria: what for? Physiology (Bethesda) 21,
233241 (2006).
7. Scorrano,L. etal. A distinct pathway remodels
mitochondrial cristae and mobilizes cytochromec
during apoptosis. Dev. Cell 2, 5567 (2002).
8. Acin-Perez,R., Fernandez-Silva,P., Peleato,M.L.,
Perez-Martos,A. &Enriquez,J.A. Respiratory active
mitochondrial supercomplexes. Mol. Cell 32,
529539 (2008).
9. Ghezzi,D. &Zeviani,M. Assembly factors of human
mitochondrial respiratory chain complexes: physiology
and pathophysiology. Adv. Exp. Med. Biol. 748,
65106 (2012).
10. DiMauro,S., Schon,E.A., Carelli,V. &Hirano,M.
Theclinical maze of mitochondrial neurology.
Nat.Rev.Neurol. 9, 429444 (2013).
11. Doimo,M. etal. Genetics of coenzyme q10 deficiency.
Mol. Syndromol. 5, 156162 (2014).
12. Nguyen,T.P. etal. Molecular characterization of the
human COQ5 Cmethyltransferase in coenzyme Q10
biosynthesis. Biochim. Biophys. Acta 1841,
16281638 (2014).
13. Allen,J.W. Cytochromec biogenesis in mitochondria
systems III and V. FEBS J. 278, 41984216 (2011).
14. DiMauro,S. &Schon,E.A. Mitochondrial disorders in
the nervous system. Annu. Rev. Neurosci. 31, 91123
(2008).
15. Mayr,J.A. etal. Spectrum of combined respiratory
chain defects. J.Inherit. Metab. Dis. 38, 41984216
(2015).
www.nature.com/nrneph
2016 Macmillan Publishers Limited. All rights reserved
REVIEWS
43. OToole,J.F. Renal manifestations of genetic
mitochondrial disease. Int. J.Nephrol. Renovasc. Dis.
7, 5767 (2014).
44. Duncan,A.J. etal. A nonsense mutation in COQ9
causes autosomal-recessive neonatal-onset primary
coenzyme Q10 deficiency: a potentially treatable form
of mitochondrial disease. Am. J.Hum. Genet. 84,
558566 (2009).
45. Lee,Y.S. etal. Mitochondrial tubulopathy: the many
faces of mitochondrial disorders. Pediatr. Nephrol. 16,
710712 (2001).
46. Gilbert,R.D. &Emms,M. Pearsons syndrome
presenting with Fanconi syndrome. Ultrastruct. Pathol.
20, 473475 (1996).
47. Ezgu,F. etal. Severe renal tubulopathy in a newborn
due to BCS1L gene mutation: effects of different
treatment modalities on the clinical course. Gene 528,
364366 (2013).
48. Gai,X. etal. Mutations in FBXL4, encoding a
mitochondrial protein, cause early-onset mitochondrial
encephalomyopathy. Am. J.Hum. Genet. 93,
482495 (2013).
49. Tucker,E.J. etal. Next-generation sequencing in
molecular diagnosis: NUBPL mutations highlight the
challenges of variant detection and interpretation.
Hum. Mutat. 33, 411418 (2012).
50. Matsutani,H. etal. Partial deficiency of cytochromec
oxidase with isolated proximal renal tubular acidosis
and hypercalciuria. Child Nephrol. Urol. 12, 221224
(1992).
51. Martin-Hernandez,E. etal. Renal pathology in
children with mitochondrial diseases. Pediatr. Nephrol.
20, 12991305 (2005).
52. Emma,F. etal. Bartter-like phenotype in
KearnsSayre syndrome. Pediatr. Nephrol. 21,
355360 (2006).
53. Goto,Y. etal. Renal tubular involvement mimicking
Bartter syndrome in a patient with KearnsSayre
syndrome. J.Pediatr. 116, 904910 (1990).
54. Visapaa,I. etal. GRACILE syndrome, a lethal
metabolic disorder with iron overload, is caused by a
point mutation in BCS1L. Am. J.Hum. Genet. 71,
863876 (2002).
55. Wilson,F.H. etal. A cluster of metabolic defects
caused by mutation in a mitochondrial tRNA. Science
306, 11901194 (2004).
56. Reilly,R.F. &Ellison,D.H. Mammalian distal tubule:
physiology, pathophysiology, and molecular anatomy.
Physiol. Rev. 80, 277313 (2000).
57. McCormick,J.A. &Ellison,D.H. Distal convoluted
tubule. Compr. Physiol. 5, 4598 (2015).
58. Simon,D.B. etal. Gitelmans variant of Bartters
syndrome, inherited hypokalaemic alkalosis, is
causedby mutations in the thiazide-sensitive NaCl
cotransporter. Nat. Genet. 12, 2430 (1996).
59. Soltoff,S.P. ATP and the regulation of renal cell
function. Annu. Rev. Physiol. 48, 931 (1986).
60. Klootwijk,E.D. etal. Mistargeting of peroxisomal
EHHADH and inherited renal Fanconis syndrome.
N.Engl. J.Med. 370, 129138 (2014).
61. Jefferson,J.A., Alpers,C.E. &Shankland,S.J.
Podocyte biology for the bedside. Am. J.Kidney Dis.
58, 835845 (2011).
62. Muller-Deile,J. &Schiffer,M. The podocyte
power-plant disaster and its contribution to
glomerulopathy. Front. Endocrinol. (Lausanne) 5, 209
(2014).
63. Saleem,M.A. 100 ways to kill a podocyte.
Nephrol.Dial. Transplant. http://dx.doi.org/10.1093/
ndt/gfu363 (2015).
64. Higgins,G.C. &Coughlan,M.T. Mitochondrial
dysfunction and mitophagy: the beginning and end
todiabetic nephropathy? Br. J.Pharmacol. 171,
19171942 (2014).
65. Che,R., Yuan,Y., Huang,S. &Zhang,A. Mitochondrial
dysfunction in the pathophysiology of renal diseases.
Am. J.Physiol. Renal Physiol. 306, F367F378
(2014).
66. Kawakami,T. etal. Deficient autophagy results in
mitochondrial dysfunction and FSGS. J.Am. Soc.
Nephrol. 26, 10401052 (2015).
67. Montini,G., Malaventura,C. &Salviati,L. Early
coenzyme Q10 supplementation in primary coenzyme
Q10 deficiency. N.Engl. J.Med. 358, 28492850
(2008).
68. Heeringa,S.F. etal. COQ6 mutations in human
patients produce nephrotic syndrome with
sensorineural deafness. J.Clin. Invest. 121,
20132024 (2011).
69. Ashraf,S. etal. ADCK4 mutations promote steroidresistant nephrotic syndrome through CoQ10
REVIEWS
118. Zsengeller,Z.K. etal. Cisplatin nephrotoxicity
involvesmitochondrial injury with impaired tubular
mitochondrial enzyme activity. J.Histochem. Cytochem.
60, 521529 (2012).
119. Funk,J.A. &Schnellmann,R.G. Persistent disruption
ofmitochondrial homeostasis after acute kidney injury.
Am. J.Physiol. Renal Physiol. 302, F853F864 (2012).
120. Zhang,Q. etal. Circulating mitochondrial DAMPs cause
inflammatory responses to injury. Nature 464,
104107 (2010).
121. Feldkamp,T., Kribben,A., Roeser,N.F., Senter,R.A.
&Weinberg,J.M. Accumulation of nonesterified fatty
acids causes the sustained energetic deficit in kidney
proximal tubules after hypoxia-reoxygenation.
Am.J.Physiol. Renal Physiol. 290, F465F477
(2006).
122. Weinberg,J.M., Venkatachalam,M.A., Roeser,N.F.
&Nissim,I. Mitochondrial dysfunction during
hypoxia/reoxygenation and its correction by
anaerobicmetabolism of citric acid cycle intermediates.
Proc.Natl Acad. Sci. USA 97, 28262831 (2000).
123. Bienholz,A. etal. Substrate modulation of fatty acid
effects on energization and respiration of kidney
proximal tubules during hypoxia/reoxygenation.
PLoSONE 9, e94584 (2014).
124. Li,S. etal. Transgenic expression of proximal tubule
peroxisome proliferator-activated receptor- in mice
confers protection during acute kidney injury. KidneyInt.
76, 10491062 (2009).
125. Tannenbaum,J., Purkerson,M.L. &Klahr,S. Effect of
unilateral ureteral obstruction on metabolism of renal
lipids in the rat. Am. J.Physiol. 245, F254F262
(1983).
126. Zager,R.A., Johnson,A.C. &Hanson,S.Y. Renal
tubular triglyercide accumulation following endotoxic,
toxic, and ischemic injury. Kidney Int. 67, 111121
(2005).
127. Cocheme,H.M. etal. Mitochondrial targeting of
quinones: therapeutic implications. Mitochondrion 7,
S94S102 (2007).
128. Kelso,G.F. etal. Selective targeting of a redox-active
ubiquinone to mitochondria within cells: antioxidant
andantiapoptotic properties. J.Biol. Chem. 276,
45884596 (2001).
129. Zhao,K. etal. Cell-permeable peptide antioxidants
targeted to inner mitochondrial membrane inhibit
mitochondrial swelling, oxidative cell death, and
reperfusion injury. J.Biol. Chem. 279, 3468234690
(2004).
130. Szeto,H.H. etal. Mitochondria-targeted peptide
accelerates ATP recovery and reduces ischemic kidney
injury. J.Am. Soc. Nephrol. 22, 10411052 (2011).
131. Mukhopadhyay,P. etal. Mitochondrial-targeted
antioxidants represent a promising approach for
prevention of cisplatin-induced nephropathy.
Free Radic. Biol. Med. 52, 497506 (2012).
132. Tang,W.X., Wu,W.H., Qiu,H.Y., Bo,H.
&Huang,S.M. Amelioration of rhabdomyolysisinduced renal mitochondrial injury and apoptosis
through suppression of Drp1 translocation. J.Nephrol.
26, 10731082 (2013).
Acknowledgements
Author contributions
All authors researched the data, made a substantial contribution to discussion of the content, wrote the article and
reviewed and/or edited the manuscript before submission.
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