Iron deficiency‐induced loss of skeletal muscle mitochondrial proteins and respiratory capacity; the role of mitophagy and secretion of mitochondria‐containing vesicles

Abstract

Iron homeostasis is essential for mitochondrial function, and iron deficiency has been associated with skeletal muscle weakness and decreased exercise capacity in patients with different chronic disorders. We hypothesized that iron deficiency‐induced loss of skeletal muscle mitochondria is caused by increased mitochondrial clearance. To study this, C2C12 myotubes were subjected to the iron chelator deferiprone. Mitochondrial parameters and key constituents of mitophagy pathways were studied in presence or absence of pharmacological autophagy inhibition or knockdown of mitophagy‐related proteins. Furthermore, it was explored if mitochondria were present in extracellular vesicles (EV). Iron chelation resulted in an increase in BCL2/Adenovirus E1B 19 kDa protein‐interacting protein 3 (BNIP3) and BNIP3‐like gene and protein levels, and the appearance of mitochondria encapsulated by lysosome‐like vesicular structures in myotubes. Moreover, mitochondria were secreted via EV. These changes were associated with cellular mitochondrial impairments. These impairments were unaltered by autophagy inhibition, knockdown of mitophagy‐related proteins BNIP3 and BNIP3L, or knockdown of their upstream regulator hypoxia‐inducible factor 1 alpha. In conclusion, mitophagy is not essential for development of iron deficiency‐induced reductions in mitochondrial proteins or respiratory capacity. The secretion of mitochondria‐containing EV could present an additional pathway via which mitochondria can be cleared from iron chelation‐exposed myotubes.

Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis

“…Iron homeostasis is indispensable to the proper function of skeletal muscle and postnatal regeneration, reflected from the importance of iron in mitochondrial respiration, ATP production, muscle contraction, and exercise capacity. This is partially due to the activity of the mitochondrial electron transport chain and mitochondrial clearance 18 . These observations could be manipulated in murine models fed with iron‐deprived diets, but muscular iron deficiency in patients is usually accompanied by secondary diseases, such as congestive heart failure and chronic obstructive pulmonary disease 19 .…”

Regulation of mitochondrial cargo-selective autophagy by posttranslational modifications

“…Deferiprone treatment causes the autophagy receptor FKBP8 on mitochondria to interact with LC3, thus initiating parkin-independent mitophagy ( 42 , 141 ). Likewise, deferiprone induces mitochondrial clearance in myotubes by hypoxia-inducible factor 1-α mediated transcriptional induction of the LC3-binding autophagy receptors BNIP3 and NIX but, interestingly, instead of autophagic degradation in this case, mitochondria were secreted as extracellular vesicles ( 142 ). Taken together, iron homeostasis is important for PINK1/parkin-independent mitochondrial clearance.…”

The effect of extracellular vesicles on the regulation of mitochondria under hypoxia

“…Thus, mitochondrial specific targeting therapy still needs a lot of work. In addition, EVs and mitochondrial-derived vesicles (MDVs) [39][40][41] can be effective mechanisms to preserve mitochondrial homeostasis, which will be discussed below (Fig. 2).…”

“…For instance, damaged mitochondria and composition can be removed by EVs 40,76 . Researchers believed that the transfer of functional mitochondria or mitochondrial compositions via EVs may increase cellular bioenergetics in ischemic endothelial cells with decreased energy levels to be strategies for treating stroke 78 .…”