Mitochondrial networking in diabetic left ventricle cardiomyocytes.
TL;DR: Original electron microscopy evidence on mitochondrial networking within diabetic left ventricular cardiomyocytes is presented, focusing on the inter-mitochondrial communication, allowing electrochemical signals transfer and outer membrane components or matrix proteins exchange.
About: This article is published in Mitochondrion.The article was published on 2017-05-01. It has received 7 citations till now. The article focuses on the topics: Cellular homeostasis & Mitochondrion.
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Journal Article•
TL;DR: Therapeutic inhibition of mitochondrial ROS by mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice, suggesting that mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.
Abstract: Introduction: The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production and subsequent oxidative damage have been implicated in the pathogenesis of diabetic cardiomyopathy. We hypothesized that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in diabetic cardiomyopathy. Hypothesis: We hypothesized that therapeutic inhibition of mitochondrial ROS with mito-TEMPO reduces diabetic cardiomyopathy. Methods: The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin (STZ)-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and single mitochondrial superoxide generation and cell death were measured. Results: Incubation with high glucose increased mitochondria superoxide generation in cultured adult cardiomyocytes, which was prevented by mito-TEMPO. Co-incubation with mito-TEMPO also abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular ROS formation and oxidative damage were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito-TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular ROS formation and oxidative damage, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts without change of blood glucose, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Mechanistic study revealed that the protective effects of mito-TMEPO were associated with down-regulation of ERK1/2 phosphorylation in diabetic hearts and high glucose-stimulated cardiomyocytes. Conclusions: Therapeutic inhibition of mitochondrial ROS by mitochondria-targeted antioxidant mito-TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in both type-1 and type-2 diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications.
146 citations
TL;DR: This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.
Abstract: Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.
33 citations
TL;DR: These findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2‐mediated mitophagy and Drp1‐regulated mitochondrial fission.
Abstract: [Cu(ttpy-tpp)Br2 ]Br (abbreviated as CTB) is a novel mitochondrion-targeting copper(II) complex synthesized by our research group, which contains tri-phenyl-phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti-tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co-immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co-ordinately promoted dynamin-related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2-mediated mitophagy and Drp1-regulated mitochondrial fission.
23 citations
TL;DR: A review of the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement, is presented in this paper, where the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.
Abstract: Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies.
14 citations
TL;DR: The focus is on the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and the effectiveness of “mitochondrial cell-penetrating/targeting peptides” as vehicles for delivery of bioactive agents into dysfunctional mitochondria.
Abstract: Besides their well-known function in cellular bioenergetics, the role of mitochondria in signaling regulation of cells homeostasis and survival has been uncovered during the past few decades. Possessing an independent genome and a unique genetic code, mitochondria biosynthesize protective stress response factors, the “mitochondrial-derived peptides,” import and deposit peptides within their matrix and are the target of peptides bound to bioactive agents, aiming at alleviation of pathology-related malfunction of the electron transport chain. As the rapidly evolving field of mitochondrial peptides is appropriate for therapeutic exploitation, a brief overview of the major recent findings is timely needed. Here, the focus is on the following issues: (i) the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, (ii) the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and (iii) the effectiveness of “mitochondrial cell-penetrating/targeting peptides” as vehicles for delivery of bioactive agents into dysfunctional mitochondria.
10 citations
Cites background from "Mitochondrial networking in diabeti..."
...Owing to their prokaryotic origin, mitochondria execute the Bquorum sensing^ coordination of intracellular processes by sending Bretrograde^ signals such as Ca2+, ROS and cytochrome C. to the other intracellular organelles and to the cytosol (Lee et al. 2013, 2015; Popov 2017)....
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References
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TL;DR: It was found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before Drp1 recruitment, suggesting that ERtubules may play an active role in defining the position of mitochondrial division sites.
Abstract: Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The endoplasmic reticulum (ER) and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.
1,622 citations
TL;DR: The ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism are reviewed.
Abstract: Mitochondrial morphology varies tremendously across cell types and tissues, changing rapidly in response to external insults and metabolic cues, such as nutrient status. The many functions of mitochondria have been intimately linked to their morphology, which is shaped by ongoing events of fusion and fission of outer and inner membranes (OM and IM). Unopposed fission causes mitochondrial fragmentation, which is generally associated with metabolic dysfunction and disease. Unopposed fusion results in a hyperfused network and serves to counteract metabolic insults, preserve cellular integrity, and protect against autophagy. Here, we review the ways in which metabolic alterations convey changes in mitochondrial morphology and how disruption of mitochondrial morphology impacts cellular and organismal metabolism.
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TL;DR: This work reviews the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.
Abstract: Mitochondria are renowned for their central bioenergetic role in eukaryotic cells, where they act as powerhouses to generate adenosine triphosphate from oxidation of nutrients. At the same time, these organelles are highly dynamic and undergo fusion, fission, transport, and degradation. Each of these dynamic processes is critical for maintaining a healthy mitochondrial population. Given the central metabolic function of mitochondria, it is not surprising that mitochondrial dynamics and bioenergetics reciprocally influence each other. We review the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.
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TL;DR: By analysis of a temperature-sensitive yeast mutant, a heat-shock protein in the matrix of mitochondria, mitochondrial hsp70 (Ssc1p), is found to be involved both in translocation of nuclear-encoded precursor proteins across the mitochondrial membranes and in (re)folding of imported proteins in the Matrix.
Abstract: By analysis of a temperature-sensitive yeast mutant, a heat-shock protein in the matrix of mitochondria, mitochondrial hsp70 (Ssc1p), is found to be involved both in translocation of nuclear-encoded precursor proteins across the mitochondrial membranes and in (re)folding of imported proteins in the matrix.
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TL;DR: It is indicated that ROS are essential signaling molecules which are required to promote health and longevity and the concept of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond.
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