Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia
Jasmine XY Khor
Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Nigel Turner
Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Sydney, Australia
Xin Y Lim
Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Miro A Astore
Center for Computational Biology and Center for Computational Mathematics, Flatiron Institute, New York, United States
Charles Perkins Centre, School of life and Environmental Sciences, University of Sydney, Sydney, Australia; Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Insulin resistance (IR) is a complex metabolic disorder that underlies several human diseases, including type 2 diabetes and cardiovascular disease. Despite extensive research, the precise mechanisms underlying IR development remain poorly understood. Previously we showed that deficiency of coenzyme Q (CoQ) is necessary and sufficient for IR in adipocytes and skeletal muscle (Fazakerley et al., 2018). Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, CoQ deficiency, mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells result in CoQ depletion and loss of mitochondrial respiratory chain components, leading to mitochondrial dysfunction and IR. Further, decreasing mitochondrial ceramide levels in vitro and in animal models (mice, C57BL/6J) (under chow and high-fat diet) increased CoQ levels and was protective against IR. CoQ supplementation also rescued ceramide-associated IR. Examination of the mitochondrial proteome from human muscle biopsies revealed a strong correlation between the respirasome system and mitochondrial ceramide as key determinants of insulin sensitivity. Our findings highlight the mitochondrial ceramide–CoQ–respiratory chain nexus as a potential foundation of an IR pathway that may also play a critical role in other conditions associated with ceramide accumulation and mitochondrial dysfunction, such as heart failure, cancer, and aging. These insights may have important clinical implications for the development of novel therapeutic strategies for the treatment of IR and related metabolic disorders.
