The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases

Abstract

Highlights What are the main findings? Macroautophagy and its selective forms play an important, multifaceted and often bidirectional role in the pathogenesis of mitochondrial diseases. The role of autophagy in cellular organelles, apart from mitophagy, has not been sufficiently investigated. What are the implications of the main findings? Restoring autophagy improves mitochondrial function and cell survival in mitochondrial disorders. Studying autophagy in cellular organelles, apart from mitochondria, has the potential to reveal new mechanisms underlying the cellular pathogenesis of mitochondrial diseases and to find new promising approaches to treatment. Abstract Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy—the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes—Kearns–Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies—as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.