The Role of ATF5 in Mitochondrial Maintenance, Biogenesis and UPRmt Signaling Following Acute Exercise in Skeletal Muscle

Abstract

Maintenance of the mitochondrial protein folding environment is essential for organellar and cellular homeostasis. Over 99% of mitochondrial proteins require import into mitochondria, followed by their folding and intraorganellar sorting. Mitochondrial stress can result in the accretion of misfolded proteins, establishing a requirement for mitochondrial protein quality control (MQC) strategies. The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment‐specific MQC mechanism that increases the expression of protective enzymes by Activating Transcription Factor 5 (ATF5) to restore mitochondrial function. Contractile activity during acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis. However, the roles of ATF5 and the UPRmtin basal mitochondrial maintenance and exercise‐induced UPRmt signaling in skeletal muscle are not known. To investigate this, we subjected WT and whole‐body ATF5 KO mice to a bout of acute exercise and collected skeletal muscle tissues immediately after. ATF5 KO animals exhibited 2‐fold increases in phosphorylated JNK protein levels, indicative of enhanced stress signaling. Interestingly, in KO muscle, PGC‐1a protein was enhanced by 50% and 40% in nuclear and cytosolic compartments, respectively, suggesting an increased drive toward mitochondrial biogenesis in the absence of ATF5. Muscle from these animals also displayed a more abundant, but dysfunctional, mitochondrial pool, with a 20% increase in mitochondrial content, 30‐40% reductions in respiration, and a 20% increase in ROS emissions, corresponding with no changes in exercise performance. The UPRmt proteins mtHSP70 and LONP were upregulated 20‐30% in KO muscle, while ATF4 mRNA was upregulated 2.5‐3.7‐fold, along with an 8% increase in its nuclear localization. Furthermore, KO muscle showed an impaired UPRmt mRNA response to acute exercise, suggesting a regulatory role for ATF5 in the maintenance of a high‐quality mitochondrial pool, and in mediating the transcription of UPRmt genes during exercise.