4.7 Article

Activating transcription factor 4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes

Journal

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 325, Issue 1, Pages C224-C242

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00080.2023

Keywords

contractile activity; lysosomal biogenesis; mitochondrial biogenesis; mitochondrial unfolded protein response; mitophagy

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Mitochondrial function is crucial for overall health and the mitochondrial unfolded protein response (UPRmt) plays a significant role in maintaining mitochondrial quality control. In this study, the transcription factor ATF4 was found to regulate mitochondrial homeostasis and myotube formation in muscle cells. ATF4 also facilitated enhanced mitochondrial networking, protein handling, and clearance of dysfunctional organelles, ultimately leading to the formation of a smaller pool of high-functioning mitochondria that are more responsive to contractile activity. These findings expand our understanding of ATF4 beyond its known functions and highlight its importance in regulating mitochondrial morphology, lysosomal biogenesis, and mitophagy in muscle cells.
Mitochondrial function is widely recognized as a major determinant of health, emphasizing the importance of understanding the mechanisms promoting mitochondrial quality in various tissues. Recently, the mitochondrial unfolded protein response (UPRmt) has come into focus as a modulator of mitochondrial homeostasis, particularly in stress conditions. In muscle, the necessity for activating transcription factor 4 (ATF4) and its role in regulating mitochondrial quality control (MQC) have yet to be determined. We overexpressed (OE) and knocked down ATF4 in C2C12 myoblasts, differentiated them to myotubes for 5 days, and subjected them to acute (ACA) or chronic (CCA) contractile activity. ATF4 mediated myotube formation through the regulated expression of myogenic factors, mainly Myc and myoblast determination protein 1 (MyoD), and suppressed mitochondrial biogenesis basally through peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1a). However, our data also show that ATF4 expression levels are directly related to mitochondrial fusion and dynamics, UPRmt activation, as well as lysosomal biogenesis and autophagy. Thus, ATF4 promoted enhanced mitochondrial networking, protein handling, and the capacity for clearance of dysfunctional organelles under stress conditions, despite lower levels of mitophagy flux with OE. Indeed, we found that ATF4 promoted the formation of a smaller pool of high-functioning mitochondria that are more responsive to contractile activity and have higher oxygen consumption rates and lower reactive oxygen species levels. These data provide evidence that ATF4 is both necessary and sufficient for mitochondrial quality control and adaptation during both differentiation and contractile activity, thus advancing the current understanding of ATF4 beyond its canonical functions to include the regulation of mitochondrial morphology, lysosomal biogenesis, and mitophagy in muscle cells.

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