Mitochondrial Diseases in the Era of Precision Medicine: Advances in Molecular Pathogenesis, Diagnosis, and Therapeutic Intervention.

Pathogenic mutations in mitochondrial DNA or nuclear genes encoding mitochondrial proteins essential for mitochondrial function give rise to mitochondrial diseases, a highly heterogeneous group of inherited multisystemic disorders. These genetic defects impair the respiratory chain and disrupt oxidative phosphorylation, resulting in critical adenosine triphosphate depletion and tissue-specific energy failure, predominantly affecting high-energy organs such as the brain, heart, and skeletal muscle. Disease pathogenesis is shaped by heteroplasmy thresholds and is further exacerbated by elevated reactive oxygen species, aberrant calcium signaling, and defective mitophagy. Although next-generation sequencing and biochemical profiling have significantly transformed diagnostic frameworks, these progressive metabolic disorders have historically been managed primarily with supportive or palliative care. Driven by precision medicine, the therapeutic paradigm has recently shifted toward genetic and organelle-targeted interventions. Advanced mitochondrial genome-editing platforms, including zinc-finger nucleases, transcription activator-like effector nucleases, and DddA-derived cytosine base editors, enable precise elimination or correction of mutant mitochondrial DNA variants, thereby modulating heteroplasmy. Concurrently, metabolic regulatory agents, mitochondria-targeted peptides, and organelle transfer techniques, encompassing germline mitochondrial replacement therapy to prevent maternal transmission and mitochondrial transplantation for tissue regeneration, are being actively investigated. Despite promising preclinical outcomes, clinical translation remains constrained by challenges in safe delivery, off-target effects, and ethical concerns associated with germline modification. This review bridges the gap between fundamental molecular pathology and cutting-edge therapeutic strategies, highlighting multidisciplinary approaches poised to transform mitochondrial disease management from symptomatic care toward prevention and disease-modifying intervention.