Diabetes Metab J.  2024 Jan;48(1):1-18. 10.4093/dmj.2023.0115.

Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases

• Zhang B
• Chang JY
• Lee MH
• Ju SH
• Yi HS
• Shong M

• KMID: 2551258
• DOI: http://doi.org/10.4093/dmj.2023.0115

Abstract

Mitochondrial stress and the dysregulated mitochondrial unfolded protein response (UPR^mt) are linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. Mitokines, signaling molecules released by mitochondrial stress response and UPR^mt, are crucial mediators of inter-organ communication and influence systemic metabolic and physiological processes. In this review, we provide a comprehensive overview of mitokines, including their regulation by exercise and lifestyle interventions and their implications for various diseases. The endocrine actions of mitokines related to mitochondrial stress and adaptations are highlighted, specifically the broad functions of fibroblast growth factor 21 and growth differentiation factor 15, as well as their specific actions in regulating inter-tissue communication and metabolic homeostasis. Finally, we discuss the potential of physiological and genetic interventions to reduce the hazards associated with dysregulated mitokine signaling and preserve an equilibrium in mitochondrial stress-induced responses. This review provides valuable insights into the mechanisms underlying mitochondrial regulation of health and disease by exploring mitokine interactions and their regulation, which will facilitate the development of targeted therapies and personalized interventions to improve health outcomes and quality of life.

Keyword

Fibroblast growth factor 21; Growth differentiation factor 15; Metabolic diseases; Mitochondria; Unfolded protein response

Figure

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  Fig. 1. Regulation of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) expression by mitochondrial stress response (MSR) and mitochondrial unfolded protein response (UPRmt). The integrated stress response (ISR) is a cellular pathway activated in response to mitochondrial defects. In this pathway, a molecule called DAP3 binding cell death enhancer (DELE) plays a crucial role. DELE activates the heme-regulated inhibitor (HRI), which leads to the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) or triggers the ISR directly. This activation of the ISR facilitates the expression of key regulatory factors, such as activating transcription factors 4 (ATF4), ATF5, and C/EBP homologous protein (CHOP), which act as crucial regulators for the expression of FGF21 and GDF15. Additionally, an elevated ratio of adenosine monophosphate (AMP)/adenosine triphosphate (ATP), signaling energy stress, can induce the activation of AMP-activated protein kinase (AMPK). This activation occurs through a potential AKT serine/threonine kinase 1 (AKT1)-mediated mechanism. Ultimately, the activation of AMPK stimulates the expression of FGF21 or GDF15, further contributing to the regulatory processes involved in MSR and UPRmt. ETC, electron transport chain.

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  Fig. 2. The pathophysiological roles of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) in the metabolic disease. FGF21 regulates appetite, enhances ketogenesis, improves insulin sensitivity, promotes lipolysis, and influences glucose homeostasis. GDF15 regulates appetite, leads to weight loss, decreases muscle mass, promotes lipolysis and fatty acid oxidation, and affects liver metabolism.

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