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Review
. 2024 Feb;65(2):55-69.
doi: 10.3349/ymj.2023.0131.

Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging

Se Hee Min  1   2 , Gil Myoung Kang  2 , Jae Woo Park  2 , Min-Seon Kim  1   3
Affiliations
Review

Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging

Se Hee Min et al. Yonsei Med J. 2024 Feb.

Abstract

Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.

Keywords: Mitochondria; aging; diabetes; hormesis; obesity; stress.

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Conflict of interest statement

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. Beneficial effects of low-grade mitochondrial stress on metabolic diseases and aging. Repeated exposure to low levels of mitochondrial stress induces a wide range of cytosolic and nuclear adaptive responses, which contribute to building resilience against higher levels of mitochondrial stress. These mitohormetic responses have been demonstrated to confer several health benefits, including the reduction of obesity and diabetes complications, delayed aging, and improved outcomes in the management of liver diseases. ROS, reactive oxygen species; UPRmt, mitochondrial unfolded protein response.
Fig. 2
Fig. 2. Molecular and cellular mechanisms of mitohormesis. Low-grade, multiple mitochondrial stresses induce mitohormetic responses that offer protection from metabolic diseases (obesity, diabetes, and liver diseases) and aging-related pathologies. These adaptive responses include ROS production, mitochondria biogenesis and dynamics (mitophagy, mitochondrial fusion and fission), alterations in mitochondrial membrane potential, activation of cytosolic Ca2+-dependent signaling pathways, mitochondrial unfolded protein responses, and inter-organ mitochondria stress response via the release of mitokines. ROS, reactive oxygen species; MDPs, mitochondria-derived peptides.
Fig. 3
Fig. 3. Examples of inter-organ mitohormetic responses. (A) In C. elegans, deletion of mitochondrial respiration component cytochrome c oxidase-1 (cco-1) in neurons extends life span by the induction of mitochondria unfolded protein responses (UPRmt) in the intestine. Secretory factors released by stressed neurons (serotonin, FLP-2, and Wnt ligand/EGL-20) mediate these inter-organ mitochondria stress responses. (B) In mice, deletion of mitochondrial ribosomal protein CRIF1 in the skeletal muscles and hypothalamic POMC neurons improves obesity, insulin resistance, and hepatic steatosis by enhancing fatty acid oxidation and lipolysis in the adipose tissue and liver. These interorgan communication in mitochondrial stress responses occur by means of mitokine GDF15 and the sympathetic nervous system.
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