Fig. 2.

Possible scenarios resulting from mitochondrial quality control failure during the progression of sarcopenia. An imbalance in mitochondrial dynamics towards fusion is associated with the appearance of giant mitochondria, characterized by highly interconnected networks, aberrant morphology, reduced bioenergetic efficiency, and increased ROS production. Enlarged mitochondria cannot be efficiently removed due to their larger size. The accumulation of lipofuscin within lysosomes further contributes to impairing the autophagosomal-lysosomal axis. Oxidants generated by dysfunctional mitochondria compromise the surrounding tissue and amplify mitochondrial damage, eventually triggering apoptosis and proteolysis via ROS-mediated activation of nuclear factor κB (NF-κB) and Forkhead box O (FoxO) (Dodd et al. 2010). These transcription factors stimulate the expression of the muscle-specific ubiquitin ligases atrogin-1 and muscle-specific RING finger 1 (MuRF-1). Protein fragments derived from the action of caspase-3 on actomyosin complexes are eventually degraded by the ubiquitin-proteasome system. A shift of dynamics towards fission leads to mitochondrial network disintegration and overactivation of mitophagy. ROS generation by fragmented mitochondria is increased, which together with the upregulation of fission, stimulates muscle protein breakdown and myonuclear apoptosis through mechanisms similar to those described above. Artwork by Francesco Antognarelli.