Extracellular Mitochondrial Components as Emerging Biomarkers and Therapeutic Targets in Human Diseases.

Mitochondria serve as the bioenergetic hub of eukaryotic cells while simultaneously acting as a major source of cellular stress and toxicity. Classical mitochondrial quality control (MQC) has long been viewed as a lysosome-dependent process centered on mitophagy. However, aging is accompanied by progressive lysosomal dysfunction, limiting the efficiency of canonical mitochondrial clearance and contributing to mitochondrial accumulation and cellular deterioration. Emerging evidence suggests that under conditions of lysosomal overload and metabolic stress, cells engage alternative quality-control pathways by selectively exporting mitochondrial components into the extracellular environment through mitochondrial-derived vesicles (MDVs) and exophers. In this review, we integrate current findings to propose a unified framework of age-associated mitochondrial disposition and discuss how cells dynamically balance intracellular degradation with extracellular mitochondrial secretion. We further examine the molecular machinery underlying MDV and exopher biogenesis and evaluate their roles in reshaping intercellular metabolic communication. Particular emphasis is placed on their translational relevance in cancer and neurodegenerative disorders, where extracellular mitochondrial trafficking may contribute to disease progression, therapeutic resistance, and tissue remodeling. We also discuss the technical and analytical bottlenecks that currently constrain this field. Finally, we discuss the emerging potential of mitochondrial secretion pathways as diagnostic biomarkers and therapeutic targets for age-associated diseases.