Exercise Improves the Coordination of the Mitochondrial Unfolded Protein Response and Mitophagy in Aging Skeletal Muscle

Abstract

The mitochondrial unfolded protein response (UPRmt) and mitophagy are two mitochondrial quality control (MQC) systems that work at the molecular and organelle levels, respectively, to maintain mitochondrial homeostasis. Under stress conditions, these two processes are simultaneously activated and compensate for each other when one process is insufficient, indicating mechanistic coordination between the UPRmt and mitophagy that is likely controlled by common upstream signals. This review focuses on the molecular signals regulating this coordination and presents evidence showing that this coordination mechanism is impaired during aging and promoted by exercise. Furthermore, the bidirectional regulation of reactive oxygen species (ROS) and AMPK in modulating this mechanism is discussed. The hierarchical surveillance network of MQC can be targeted by exercise-derived ROS to attenuate aging, which offers a molecular basis for potential therapeutic interventions for sarcopenia.

L-Theanine Prolongs the Lifespan by Activating Multiple Molecular Pathways in Ultraviolet C-Exposed Caenorhabditis elegans

“…It has been documented that stresses inducing mitophagy can concurrently trigger the activation of the mitochondrial unfolded protein response (UPR mt ) [ 47 ]. The UPR mt serves as a signaling pathway from the mitochondria to the nucleus, initiated by the buildup of unfolded proteins within the mitochondria, and ultimately leading to the upregulation of mitochondrial protective genes such as molecular chaperones and proteases [ 48 , 49 ].…”

Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function inDrosophila

“…This was accompanied by improved performance in locomotion, reflecting preserved motor functions in aged mice. Beyond these, UPR MT regulates hippocampal neural stem cell aging, with implications for cognitive functions 55 and affects skeletal muscle aging, as exercise improves coordination of UPR MT and mitophagy in aging skeletal 56 . Moreover, it plays a critical role in fertility and reproductive aging 57 suggesting that UPR MT disruption can pivot healthy aging towards pathological states.…”

Life-Long Aerobic Exercise is a Non-Pharmacological Approach for Inducing Autophagy and Delaying Muscle Atrophy in the Aging Population

“…Under typical circumstances, homeostasis in mitochondrial mass is maintained by constant dynamic fluctuations in mitochondrial biogenesis, kinetics, and autophagy. Among these, aged myasthenia gravis is significantly influenced by mitochondrial dynamics [9]. Its core apparatus is made up of mitochondrial dynamicsrelated protein 1 (Drp1) in the mitochondrial division core apparatus and fusion proteins (Mitofusin 2, Mfn2) in the outer mitochondrial membrane.…”