The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

Dabravolski, Siarhei A.; Sadykhov, Nikolay K.; Kartuesov, Andrey G.; Borisov, Evgeny E.; Sukhorukov, Vasily N.; Orekhov, Alexander N.

doi:10.3390/ijms23147863

Cited by 16 publications

(14 citation statements)

References 111 publications

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“…Since several recent studies have reported that diabetes is affected by mitophagy [ 5 , 6 , 13 , 17 , 22 , 23 , 25 , 31 ], we hypothesized that Parkin could play an important role in mitochondria in pancreatic cells in diabetes. We observed many mitophagy-related vesicles in Beta TC-6 islet cell lines treated with streptozotocin (STZ) diabetes stress through electron microscopy ( Fig 1A and 1B ).…”

Section: Resultsmentioning

confidence: 99%

Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells

Shim

Chung

Jung³

et al. 2023

PLoS ONE

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Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.

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Section: Resultsmentioning

confidence: 99%

Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells

Shim

Chung

Jung³

et al. 2023

PLoS ONE

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“…Increased lipids may promote cardiomyocyte death induced by lipotoxicity due to limited FFA oxidation ( 3 , 44 ). In addition, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced more frequently as a result of increased intracellular fatty acid content and mitochondrial malfunction, which in turn increases OS and ERS and inhibits autophagy ( 20 , 45 , 46 ). The interaction of these effects causes ECM remodeling and fibrosis, along with cardiomyocyte loss, cardiac enlargement, and inflammation ( 47 ).…”

Section: Diabetic Cardiomyopathy: Pathogenesis Disease Progression An...mentioning

confidence: 99%

“…The interaction of these effects causes ECM remodeling and fibrosis, along with cardiomyocyte loss, cardiac enlargement, and inflammation ( 47 ). Heart stiffness, poor cardiac relaxation, and diastolic dysfunction are early signs of DCMP caused by pathophysiological anomalies ( 46 ). In addition, accumulated lipids in ECs may decrease nitric oxide (NO) bioavailability, promoting endothelial dysfunction and accelerating atherosclerosis ( 9 ).…”

Section: Diabetic Cardiomyopathy: Pathogenesis Disease Progression An...mentioning

confidence: 99%

Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs

et al. 2023

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Diabetes mellitus (DM) is on the rise, necessitating the development of novel therapeutic and preventive strategies to mitigate the disease’s debilitating effects. Diabetic cardiomyopathy (DCMP) is among the leading causes of morbidity and mortality in diabetic patients globally. DCMP manifests as cardiomyocyte hypertrophy, apoptosis, and myocardial interstitial fibrosis before progressing to heart failure. Evidence suggests that non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), regulate diabetic cardiomyopathy-related processes such as insulin resistance, cardiomyocyte apoptosis and inflammation, emphasizing their heart-protective effects. This paper reviewed the literature data from animal and human studies on the non-trivial roles of miRNAs and lncRNAs in the context of DCMP in diabetes and demonstrated their future potential in DCMP treatment in diabetic patients.

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“…DM has been reported to induce cardiac dysfunction (DM cardiomyopathy (DCM)) due to mitochondrial dysfunction [ 6 ]. Individuals with DCM are associated with an increasing risk of AF.…”

Section: Introductionmentioning

confidence: 99%

Disturbed Cardiac Metabolism Triggers Atrial Arrhythmogenesis in Diabetes Mellitus: Energy Substrate Alternate as a Potential Therapeutic Intervention

Lkhagva

Lee

Lin

et al. 2022

Cells

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Atrial fibrillation (AF) is the most common type of sustained arrhythmia in diabetes mellitus (DM). Its morbidity and mortality rates are high, and its prevalence will increase as the population ages. Despite expanding knowledge on the pathophysiological mechanisms of AF, current pharmacological interventions remain unsatisfactory; therefore, novel findings on the underlying mechanism are required. A growing body of evidence suggests that an altered energy metabolism is closely related to atrial arrhythmogenesis, and this finding engenders novel insights into the pathogenesis of the pathophysiology of AF. In this review, we provide comprehensive information on the mechanistic insights into the cardiac energy metabolic changes, altered substrate oxidation rates, and mitochondrial dysfunctions involved in atrial arrhythmogenesis, and suggest a promising advanced new therapeutic approach to treat patients with AF.

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The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

Cited by 16 publications

References 111 publications

Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells

Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells

Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs

Disturbed Cardiac Metabolism Triggers Atrial Arrhythmogenesis in Diabetes Mellitus: Energy Substrate Alternate as a Potential Therapeutic Intervention

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