Mitochondrial Quality Control as the Mechanistic Hinge of Inherited Cardiomyopathy: Convergent Pathobiology and Targeted Therapy

Abstract

Inherited mitochondrial cardiomyopathies arise from pathogenic variants that disrupt oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin biogenesis, or mitochondrial dynamics and quality control. Although the causative genes are diverse—mtDNA mutations, nuclear respiratory-chain and assembly factors, TAZ in Barth syndrome, FXN in Friedreich ataxia, AGK in Sengers syndrome—the resulting cardiac disease converges on a shared endpoint: bioenergetic insufficiency with cristae destabilization, calcium mishandling, redox imbalance, and failure of mitophagy-dependent quality control. We synthesize how these distinct lesions funnel into common pathways of hypertrophy, fibrosis, and arrhythmogenesis, and argue that this convergence, rather than any single gene, defines the actionable therapeutic space. Mapping treatment onto these nodes, we discuss cardiolipin-directed stabilization with elamipretide—approved for Barth syndrome in 2025—gene-replacement and editing strategies (AAV-delivered TAZ and FXN, mitochondrial base editing), and cofactor, substrate-bypass, and mitophagy-modulating approaches. We propose a falsifiable central hypothesis with testable predictions, and confront the field’s principal obstacles: genetic heterogeneity requiring patient stratification, an apparent fibrotic ceiling on reversibility, and mitochondrial delivery barriers. Positioning mitochondrial quality control as the mechanistic hinge, we outline a stratified, mechanism-guided route toward cardiac-specific therapy.