Mitochondrial Disorders in Kidney Diseases

Mitochondrial Disorders

• Mitochondrial genetic mutations affect renal function, causing acute and chronic kidney diseases.
• The mitochondrial genome encodes 13 of the 88 protein subunits of ETC complexes I through V, 22 mitochondrial-specific transfer RNAs (tRNAs), and two RNA components of the translational apparatus.
• The nuclear genome encodes the remaining respiratory chain subunits and most of the mitochondrial DNA replication and expression components.

Incidence and Characteristics of Mitochondrial Disorders

• The incidence of genetic mitochondrial disorders is estimated at about 1 in 5000 births.
• The most common disorders affect the sequence of a mitochondrial tRNA for leucine.
• Symptoms are evident before 2 months of age, and the number of organ systems affected increases with age.
• Impaired mitochondrial oxidative phosphorylation results in increased levels of reducing equivalents (NADH, FADH), leading to elevated levels of lactic acid, ketone bodies, and impaired redox status.

Clinical Manifestations of Mitochondrial Disease

• Myopathies and cardiomyopathies are the most common manifestations of mitochondrial disease.
• Central nervous system symptoms, including encephalopathies, are very common.
• Renal system impairment is present but is not seen without other system deficiencies and is usually reported in children.
• Impairment of proximal tubule reabsorption, known as de Toni–Debré–Fanconi syndrome, is the most frequently observed renal manifestation.

Mitochondrial Function in Diabetic Kidneys

• Significant changes in mitochondrial function have been described in diabetic kidneys.
• Early changes in mitochondrial energetics, increased mitochondrial fragmentation, and reduced levels of PGC1a have been described.
• Increased metabolism has been shown to be associated with mitochondrial dysfunction in diabetic nephropathy.

Mitochondrial Function in CKD and AKI

• Dysfunction of ETC proteins in mitochondria from diabetic kidneys leads to less efficient ATP production and compensatory increases in glucose and fatty acid metabolic flux.
• Mitochondrial dysfunction has been observed in nondiabetic CKD.
• Early changes in mitochondrial function and structure have been reported in animal models of CKD.
• Mitochondrial DNA copy number has been evaluated in peripheral blood in a population cohort, and participants with higher mitochondrial DNA copy numbers had a lower rate of prevalent diabetes and lower risk of incident CKD.
• Mitochondrial dysfunction plays a significant role in AKI, with decreased mitochondrial mass, disruption of cristae, and significant mitochondrial swelling observed in ischemic and nephrotoxic AKI.

This quiz covers the role of mitochondrial dysfunction in acute and chronic kidney diseases, including genetic mutations affecting mitochondrial function and their renal manifestations.