Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control

Abstract

In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy-lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy-lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline.

Keywords: autophagy; cytokine; endolysosomal system; hepcidin; inflammation; labile iron; mitophagy; physical performance; sarcopenia; transferrin.

Figure 1

Mechanisms of iron transport and mitochondrial homeostasis. Dietary heme iron and ferrous iron (Fe²⁺) are absorbed by duodenal enterocytes and transferred into the bloodstream. Herein, iron binds Apo-transferrin (Apo-Tf), which allows for its mobilization. For cellular iron uptake, the ferric iron (Fe³⁺)–Tf complex binds to Tf receptor 1 (TfR1) at the plasma membrane and is internalized via a clathrin-coated vesicle. Iron released from Apo-Tf composes the cytoplasmic pool of labile iron that can be stored bound to ferritin (Fer) or can enter the mitochondria and form iron–sulfur (Fe–S) clusters and heme required for electron transport chain complexes. In response to low intracellular iron levels, nuclear receptor coactivator 4 (NCOA4) induces ferritinophagy, which can trigger Fe²⁺ overload and consequently reactive oxygen species (ROS) burst. The latter triggers ferroptosis, mitochondrial damage, and fission. To preserve mitochondrial homeostasis, damaged mitochondria, depending on damage severity, can undergo mitophagy and/or release mitochondria-derived vesicle (MDV) containing oxidized proteins and nucleic acids. In the cytosol, MDVs can form multivesicular bodies (MVBs) that can either pursue endolysosomal degradation or give rise to extracellular vesicles (EVs) released outside the cell. Red-dashed arrows highlight the pathways that are more relevant to iron dyshomeostasis and alterations in mitochondrial quality control. Abbreviations: BNIP3, BCL2-interacting protein 3; CP, ceruloplasmin; DcytB, duodenal cytochrome b; DMT1, divalent metal transporter 1; FPN, ferroportin; FtMt, mitochondrial ferritin; FUNDC1, FUN14 domain-containing protein 1; HCP1, heme carrier protein 1; HEPH, hephaestin; LIP, labile iron pool; MFRN, mitoferrin; NIX, NIP-3-like protein X; PINK1, PTEN-induced kinase 1; STEAP3, six-transmembrane epithelial antigen of prostate 3; Ub, ubiquitin. Created in https://BioRender.com (accessed on 24 April 2025).