Primary Mitochondrial-Disorders-Associated Nephropathy in Adulthood

Abstract

Oxidative phosphorylation (OXPHOS) is the main source of cellular adenosine triphosphate (ATP) production and depends on proteins encoded by both mitochondrial and nuclear DNA (nDNA). Pathogenic variants affecting this dual genetic control cause primary mitochondrial disorders (MIDs), which follow either maternal inheritance when they affect mitochondrial DNA (mtDNA) or autosomal inheritance when they affect nuclear-encoded mitochondrial proteins. Once considered predominantly pediatric conditions, these disorders are increasingly recognized in adults where their clinical presentation is heterogeneous and frequently underdiagnosed, requiring the involvement of various medical specialties.Because of their high energy requirements, kidneys are particularly vulnerable to primary MIDs. Tubular epithelial cells rely on OXPHOS for solute transport, whereas podocytes require sustained ATP production to preserve the glomerular filtration barrier. Although kidney involvement in adult primary MIDs has long been regarded as rare, emerging data indicate that primary MIDs–associated nephropathy (MIDAN) is more common than previously appreciated, yet remains under-recognized, as a cause of adult kidney disease. Renal manifestations include a broad spectrum of glomerular disorders—predominantly focal segmental glomerulosclerosis (FSGS), often associated with diabetes mellitus and sensorineural hearing impairment—as well as tubulo-interstitial nephritis (TIN), which may present as an isolated renal phenotype or as part of a multisystemic disorder.Advances in next-generation sequencing, including mitochondrial genome sequencing and exome or whole-genome sequencing, are transforming the diagnostic approach to MIDAN. Improved recognition of mitochondrial etiologies in adults with unexplained glomerular or tubulo-interstitial kidney disease is essential to optimize diagnosis, management, and genetic counseling.