Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy

Westermeier, Francisco; Navarro-Márquez, Mario; López-Crisosto, Camila; Bravo-Sagua, Roberto; Quiroga, Clara; Bustamante, Mario; Verdejo, Hugo; Zalaquett, Ricardo; Ibacache, Mauricio; Parra, Valentina; Castro, Pablo; Rothermel, Beverly A.; Hill, Joseph A.; Lavandero, Sergio

doi:10.1016/j.bbamcr.2015.02.005

Cited by 52 publications

(39 citation statements)

References 85 publications

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“…2A, B). Although no direct link was made between mitochondrial damage and cardiomyocyte insulin resistance in this study, other researchers have suggested that insulin resistance is downstream of mitochondrial dysfunction in models of diabetic cardiomyopathy (68,69).…”

Section: Discussioncontrasting

confidence: 58%

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

et al. 2018

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Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain-length dependent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria-targeted ceramides led to mitophagy in a manner proportional to N-acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.-Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.

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Section: Discussioncontrasting

confidence: 58%

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

et al. 2018

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“…Insulin inhibits FOXO1 activity, thereby maintaining the integrity of the mitochondrial electron transport chain (METC) and the ratio of NAD +/NADH [18] and protecting mitochondrial function. Therefore, insulin and mitochondria are interdependent; mitochondria require insulin for normal function, mitochondria are required for insulin signaling [99], and skeletal structure and function disorders in aging skeletal muscle increase the risk of insulin resistance.…”

Section: Mitochondrial Dysfunction Can Increase the Risk Of Insulin Rmentioning

confidence: 99%

Mechanism of increased risk of insulin resistance in aging skeletal muscle

Shou

Chen

Xiao

2020

Diabetol Metab Syndr

167

112

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As age increases, the risk of developing type 2 diabetes increases, which is associated with senile skeletal muscle dysfunction. During skeletal muscle aging, mitochondrial dysfunction, intramyocellular lipid accumulation, increased inflammation, oxidative stress, modified activity of insulin sensitivity regulatory enzymes, endoplasmic reticulum stress, decreased autophagy, sarcopenia and over-activated renin-angiotensin system may occur. These changes can impair skeletal muscle insulin sensitivity and increase the risk of insulin resistance and type 2 diabetes during skeletal muscle aging. This review of the mechanism of the increased risk of insulin resistance during skeletal muscle aging will provide a more comprehensive explanation for the increased incidence of type 2 diabetes in elderly individuals, and will also provide a more comprehensive perspective for the prevention and treatment of type 2 diabetes in elderly populations.

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“…In endothelial cells, mitochondrial fission also contributes to the reduction in eNOS-derived NO bioavailability (9), impairment of angiogenesis (10), and induction of apoptosis (11). Furthermore, an increase in mitochondrial fission is associated with the pathogenesis of diabetic cardiomyopathy (12), nephropathy (13), and peripheral neuropathy (14). …”

Section: Introductionmentioning

confidence: 99%

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission

et al. 2016

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Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

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Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy

Cited by 52 publications

References 85 publications

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

Lipotoxic very‐long‐chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

Mechanism of increased risk of insulin resistance in aging skeletal muscle

Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission

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