Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense.

Autor:	Igual Gil C; Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.; Institute of Nutritional Science, University of Potsdam, Potsdam, Germany., Löser A; Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.; TraceAge-Deutsche Forschungsgemeinschaft (DFG) Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany., Lossow K; Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.; TraceAge-Deutsche Forschungsgemeinschaft (DFG) Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany., Schwarz M; Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.; TraceAge-Deutsche Forschungsgemeinschaft (DFG) Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany., Weber D; Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany., Grune T; TraceAge-Deutsche Forschungsgemeinschaft (DFG) Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany.; Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany., Kipp AP; Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.; TraceAge-Deutsche Forschungsgemeinschaft (DFG) Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany., Klaus S; Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.; Institute of Nutritional Science, University of Potsdam, Potsdam, Germany., Ost M; Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.; Paul Flechsig Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2023 Oct 23; Vol. 14, pp. 1277866. Date of Electronic Publication: 2023 Oct 23 (Print Publication: 2023).
DOI:	10.3389/fendo.2023.1277866
Abstrakt:	Mitochondria play multifaceted roles in cellular function, and impairments across domains of mitochondrial biology are known to promote cellular integrated stress response (ISR) pathways as well as systemic metabolic adaptations. However, the temporal dynamics of specific mitochondrial ISR related to physiological variations in tissue-specific energy demands remains unknown. Here, we conducted a comprehensive 24-hour muscle and plasma profiling of male and female mice with ectopic mitochondrial respiratory uncoupling in skeletal muscle (m Ucp1 -transgenic, TG). TG mice are characterized by increased muscle ISR, elevated oxidative stress defense, and increased secretion of FGF21 and GDF15 as ISR-induced myokines. We observed a temporal signature of both cell-autonomous and systemic ISR in the context of endocrine myokine signaling and cellular redox balance, but not of ferroptotic signature which was also increased in TG muscle. We show a progressive increase of muscle ISR on transcriptional level during the active phase (night time), with a subsequent peak in circulating FGF21 and GDF15 in the early resting phase. Moreover, we found highest levels of muscle oxidative defense (GPX and NQO1 activity) between the late active to early resting phase, which could aim to counteract excessive iron-dependent lipid peroxidation and ferroptosis in muscle of TG mice. These findings highlight the temporal dynamics of cell-autonomous and endocrine ISR signaling under skeletal muscle mitochondrial uncoupling, emphasizing the importance of considering such dissociation in translational strategies and sample collection for diagnostic biomarker analysis. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Igual Gil, Löser, Lossow, Schwarz, Weber, Grune, Kipp, Klaus and Ost.)
Databáze:	MEDLINE
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