The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes

Dabravolski, Siarhei A.; Orekhova, Varvara A.; Baig, Mirza S.; Bezsonov, Evgeny E.; Starodubova, A. V.; Popkova, T.; Orekhov, Alexander N.

doi:10.3390/ijms22136733

Cited by 30 publications

(17 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since mtDNA is present in several copies within the cell, mtDNA mutations can be homo-or heteroplasmic, and the latter are characterized by certain heteroplasmy level, at which phenotypic effects of the mutation become apparent. Both spontaneously acquired and inherited mtDNA mutations can contribute to human disease development, with MIDD and MELAS being examples of maternally inherited mitochondrial diseases [10,55]. The list of mtDNA variants implicated in human disease is constantly growing.…”

Section: Mtdna Mutations In Atherosclerosis and Related Pathologiesmentioning

confidence: 99%

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Salnikova

Orekhova

Grechko

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.

show abstract

Section: Mtdna Mutations In Atherosclerosis and Related Pathologiesmentioning

confidence: 99%

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Salnikova

Orekhova

Grechko

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…An abnormal mitochondrial morphology and reduced GSIS have been found in β cells from postmortem T2D patients [8][9][10]. Impairments in OxPhos [16,28,29] and diminished mitochondrial activity have been demonstrated in diabetes patients [2,4,11,12,27,[30][31][32][33][34][35], while mutations in the mitochondrial genome such as the mtDNA 3243 mutation were shown to be associated with diabetes [36][37][38][39][40]. More specifically, OxPhos genes were differentially expressed, and DNA methylation was found in these genes in islets from patients with T2D compared with nondiabetic donors [13,14].…”

Section: Discussionmentioning

confidence: 99%

Cytochrome c Oxidase Activity as a Metabolic Regulator in Pancreatic Beta-Cells

Aharon-Hananel

Romero-Afrima

Saada

et al. 2022

Cells

View full text Add to dashboard Cite

Pancreatic β-cells couple glucose-stimulated insulin secretion (GSIS) with oxidative phosphorylation via cytochrome c oxidase (COX), a mitochondrial respiratory-chain enzyme. The Cohen diabetic-sensitive (CDs) rats exhibit hyperglycemia when fed a diabetogenic diet but maintain normoglycemia on a regular diet. We have previously reported a decreased COX activity in CDs rats and explored its relevance for type 2 diabetes (T2D). In this study, we investigated the relation between COX activity in islets, peripheral-blood mononuclear cells (PBMCs), and GSIS during diabetes development in CDs rats fed a diabetogenic diet for 4, 11, 20, and 30 days and during reversion to normoglycemia in hyperglycemic CDs rats fed a reversion diet for 7, 11, and 20 days. An oral glucose-tolerance test was performed at different periods of the diets measuring blood glucose and insulin concentrations. COX activity was determined in islets and PBMCs isolated from rats at the different periods of the diets. We demonstrated a progressive reduction in COX activity in CDs-islets that correlated positively with the decreasing GSIS (R2 = 0.9691, p < 0.001) and inversely with the elevation in blood glucose levels (R2 = 0.8396, p < 0.001). Hyperglycemia was initiated when islet COX activity decreased below 46%. The reversion diet restored >46% of the islet COX activity and GSIS while re-establishing normoglycemia. Interestingly, COX activity in PBMCs correlated significantly with islet COX activity (R2 = 0.8944, p < 0.001). Our data support islet COX activity as a major metabolic regulator of β-cells function. The correlation between COX activity in PBMCs and islets may serve as a noninvasive biomarker to monitor β-cell dysfunction in diabetes.

show abstract

“…Indeed, the impact of mitochondrial DNA mutations is most pronounced in tissues with a low mitotic rate and high ATP production, such as islet cells. Pathophysiologically, there are in total 54 known mtDNA mutations (deletions, substitutions and point mutations) implicated in diabetes development [ 68 ]. Among these, the most frequently encountered is the A to G substitution at position bp3243 (A3243G) in a gene encoding for tRNA of leucine [ 69 ].…”

Section: β-Cell Mitochondria In Diabetes Mellitusmentioning

confidence: 99%

β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

et al. 2022

View full text Add to dashboard Cite

Diabetes mellitus (DM), currently affecting 463 million people worldwide is a chronic disease characterized by impaired glucose metabolism resulting from the loss or dysfunction of pancreatic β-cells with the former preponderating in type 1 diabetes (T1DM) and the latter in type 2 diabetes (T2DM). Because impaired insulin secretion due to dysfunction or loss of pancreatic β-cells underlies different types of diabetes, research has focused its effort towards the generation of pancreatic β-cells from human pluripotent stem cell (hPSC) as a potential source of cells to compensate for insulin deficiency. However, many protocols developed to differentiate hPSCs into insulin-expressing β-cells in vitro have generated hPSC-derived β-cells with either immature phenotype such as impaired glucose-stimulated insulin secretion (GSIS) or a weaker response to GSIS than cadaveric islets. In pancreatic β-cells, mitochondria play a central role in coupling glucose metabolism to insulin exocytosis, thereby ensuring refined control of GSIS. Defects in β-cell mitochondrial metabolism and function impair this metabolic coupling. In the present review, we highlight the role of mitochondria in metabolism secretion coupling in the β-cells and summarize the evidence accumulated for the implication of mitochondria in β-cell dysfunction in DM and consequently, how targeting mitochondria function might be a new and interesting strategy to further perfect the differentiation protocol for generation of mature and functional hPSC-derived β-cells with GSIS profile similar to human cadaveric islets for drug screening or potentially for cell therapy.

show abstract

The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes

Cited by 30 publications

References 94 publications

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Cytochrome c Oxidase Activity as a Metabolic Regulator in Pancreatic Beta-Cells

β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?

Contact Info

Product

Resources

About