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Review
, 12 (5), 267-80

Mitochondrial Dysfunction in Inherited Renal Disease and Acute Kidney Injury

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Review

Mitochondrial Dysfunction in Inherited Renal Disease and Acute Kidney Injury

Francesco Emma et al. Nat Rev Nephrol.

Abstract

Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, 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, mitochondrial diseases 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. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Mitochondrial energy metabolism and the respiratory chain
Acetyl-coenzyme A (Acetyl-CoA) is the terminal product of carbohydrate and lipid metabolism, and is oxidized through the reactions of the Krebs cycle to produce CO2. The high 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+) across the 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.
Figure 2
Figure 2. Interplay of mitochondrial and nuclear genes in the biogenesis of the respiratory chain
Mitochondrial (mt) DNA encodes 13 structural subunits of the respiratory chain complexes (red ovals) as well as two ribosomal (r)RNAs and 22 transfer (t)RNAs that are required for mitochondrial protein synthesis. Nuclear (n)DNA encodes all the other structural subunits of the respiratory chain complexes, cytochrome c, assembly factors, the enzymes required for coenzyme Q (CoQ) biosynthesis and proteins involved in mtDNA replication and maintenance and in mitochondrial protein synthesis.
Figure 3
Figure 3. Electron microscopy images of a renal biopsy sample obtained from a patient with a COQ2 mutation
a | The parietal epithelium of the Bowman capsule (arrowheads) appears healthy and contains a normal number of mitochondria. By contrast, the urinary space is occupied by swollen podocytes (asterisk) that show extensive foot-process fusion (arrows). b | Enlarged view of a podocyte showing the cytoplasm packed with mitochondria, several of which are dysmorphic.
Figure 4
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 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 co-activator peroxisome proliferator-activated receptor-γ co-activator 1-α (PGC-1-α). Examples of potential preventive and therapeutic strategies are highlighted in pink boxes. mtDNA, mitochondrial DNA.

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