Mitochondrial electron transport chain, ceramide and Coenzyme Q are linked in a pathway that drives insulin resistance in skeletal muscle

Abstract

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. Here, we provide new insights into the mechanistic connections between cellular alterations associated with IR, including increased ceramides, deficiency of coenzyme Q (CoQ), mitochondrial dysfunction, and oxidative stress. We demonstrate that elevated levels of ceramide in the mitochondria of skeletal muscle cells results 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 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.

The relationship of sphingolipid mechanisms with oxidative stress and changes in mitochondria during functional unloading of postural muscles

“…Наблюдаемый нами эффект также согласуется с данными литерату- Роль церамида в регуляции митохондриальной функции и ингибировании комплексов дыхательной цепи ранее многократно обсуждалась в различных исследованиях. Например, некоторые данные указывают на то, что церамиды могут ингибировать I, III и IV комплексы дыхательной цепи с параллельным образованием АФК [9][10][11]. Снижение митохондриального дыхания в экспериментах с двухнедельной разгрузкой скелетных мышц O.S.…”

“…Известно, что образование церамида может происходить в рамках трёх основных путей, таких как синтез в эндоплазматическом ретикулуме (путь de novo), гидролиз сфингомиелина при участии сфингомиелиназ и реалкилирование сфингозина («salvage pathway») [8]. В ряде исследований представлены убедительные доказательства того, что повышение активности сфингомиелиназного пути с последующим накоплением церамида может опосредовать развитие как окислительного стресса, так и митохондриальной дисфункции [9][10][11].…”

Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action

“…Experiments were conducted using Mycoplasma-free L6 myotubes overexpressing HA-GLUT4 cell lines. HA-GLUT4 overexpression is crucial for investigating insulin sensitivity in vitro, as previously outlined 90 . L6-myoblasts were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 2 mM GlutaMAX at 37°C with 10% CO2.…”

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

“…Mitochondria, abundant organelles in most cells, consist of specialized component with multiple physiological functions: the outer mitochondrial membrane, the interstitial mitochondrial membrane, the inner mitochondrial membrane, and the mitochondrial matrix. T2DM is closely related to various forms of mitochondrial dysfunction, including abnormal energy metabolism, imbalance in calcium signal transduction, increased production of reactive oxygen species (ROS), impaired mitochondrial dynamics, and mitophagy ( Dadsena et al, 2019 ; Diaz-Vegas et al, 2023 ). These dysfunctions can exacerbate insulin resistance and induce cell apoptosis by impacting energy metabolism and promoting oxidative stress.…”

“…This leads to the release of cytochrome c, inducing mitochondrial dysfunction ( Dadsena et al, 2019 ). For example, elevated ceramide levels in the mitochondria of skeletal muscle cells cause coenzyme Q depletion and loss of the mitochondrial respiratory chain components, resulting in mitochondrial dysfunction and insulin resistance ( Diaz-Vegas et al, 2023 ). Ceramides can directly transfer to mitochondria through the mitochondria-associated membrane (MAM).…”