scholarly journals MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction

2005 ◽  
Vol 118 (22) ◽  
pp. 5357-5367 ◽  
Author(s):  
N. Nakashima-Kamimura
Keyword(s):  
Mitochondrial Dysfunction ◽  
Gene Product ◽  
Nuclear Gene ◽  
Mitochondrial Mass

Abstract 269: Cardiac Specific Disruption of Drp-1 Causes the Development of Cardiac Dysfunction via Inhibition of Autophagy and Induction of Apoptosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Yoshiyuki Ikeda ◽  
Junichi Sadoshima
Keyword(s):  
Mitochondrial Dysfunction ◽  
Systolic Function ◽  
Mitochondrial Fission ◽  
Mitochondrial Mass ◽  
Reduced Ejection Fraction ◽  
Tibia Length ◽  
Cardiac Systolic Function

Fission and fusion affect mitochondrial turnover in part by modulating mitophagy. This study aimed to clarify the role of mitochondrial fission in regulating cardiac function and autophagy in the heart. Dynamin-related protein 1 (Drp-1) plays an essential role in mediating mitochondrial fission. Therefore, we generated cardiac specific Drp-1 KO mice and utilized cultured cardiomyocytes transduced with adenovirus harboring short hairpin Drp-1 (Ad-shDrp-1) to test the effect of Drp-1 disruption both in vivo and in vitro. In Drp-1 KO hearts we observed a significantly greater mitochondrial mass ratio compared to control, as assessed by electron microscopy (Drp-1 KO: 3.57 ± 1.38, control: 1.18 ± 0.31, P<0.05). Mitochondrial ATP content was significantly lower (0.70 ± 0.07 vs 1.03 ± 0.10, P<0.05), while mitochondrial swelling was significantly greater (% decrease in absorbance; 8.01 ± 1.99 vs 2.01 ± 0.58, P<0.05) in Drp-1 KO hearts versus control. Mitochondrial membrane potential, assessed by JC-1 staining, was significantly reduced in myocytes with knockdown of Drp-1. Taken together, these results suggest that inhibition of fission causes mitochondrial dysfunction. We also examined the effect of Drp-1 depletion on autophagy. We found that the amount of LC-3 II was significantly less (0.47 ± 0.16 vs 1.32 ±0.34, P<0.05), whereas p62 expression was significantly greater (1.14 ± 0.16 vs 0.16 ± 0.06, P<0.01) in Drp-1 KO hearts compared to control. The number of LC3 dots in Ad-shDrp-1 transduced myocytes was lower than that of sh-scramble treatment. We investigated apoptosis and found that the amount of cleaved caspase-3 (0.62 ± 0.24 vs 0.18 ± 0.04, P<0.05) and the number of TUNEL positive cells (0.22 ± 0.12 vs 0.03 ± 0.06%, P<0.01) were higher in Drp-1 KO versus control hearts. Cardiac systolic function was reduced (ejection fraction; 44.5 ± 6.3 vs 85.4 ± 5.7%, P<0.01) and LVW/tibia length was greater (4.48 ± 0.38 vs 3.84 ± 0.58, P<0.05) in Drp-1 KO mice compared to control. Finally, we observed that the survival rate of Drp-1 KO mice was significantly reduced compared to control mice. Our results demonstrate that inhibition of mitochondrial fission via disruption of Drp-1 inhibits autophagy and causes mitochondrial dysfunction, thereby promoting cardiomyopathy.

A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging

2020 ◽  
Author(s):  
Li Gao ◽  
Min Wang ◽  
Linfeng Liao ◽  
Na Gou ◽  
Piao Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Nuclear Gene ◽  
Redox System ◽  
Premature Aging ◽  
Motor Deficit ◽  
Mitochondria Dysfunction ◽  
Respiratory Chain Enzyme ◽  
Knock Out ◽  
Mtdna Mutations

Abstract The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

scholarly journals Mitophagy and Mitochondrial Dysfunction in Cancer

2020 ◽  
Vol 4 (1) ◽  
pp. 41-60 ◽  
Author(s):  
Kay F. Macleod
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cell Fate ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Tumor Cell Growth ◽  
Mitochondrial Mass ◽  
Cell Fate Decisions ◽  
Signaling Mechanisms ◽  
Altered Cell

The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and BNIP3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.

scholarly journals Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda F. C. Lopes
Keyword(s):  
Dna Methylation ◽  
Mitochondrial Dysfunction ◽  
Nuclear Dna ◽  
Tricarboxylic Acid Cycle ◽  
Nuclear Gene ◽  
Nuclear Gene Expression ◽  
One Step ◽  
Methionine Pathway ◽  
One Carbon Metabolism ◽  
The One

AbstractMitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mitochondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored. Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes.

scholarly journals Mitochondrial retrograde signalling in neurological disease

2020 ◽  
Vol 375 (1801) ◽  
pp. 20190415 ◽  
Author(s):  
Lucy Granat ◽  
Rachel J. Hunt ◽  
Joseph M. Bateman
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Neurodevelopmental Disorders ◽  
Neurological Disease ◽  
Neurological Diseases ◽  
Nuclear Gene ◽  
Mitochondrial Diseases ◽  
Autism Spectrum ◽  
Signalling Pathways ◽  
Retrograde Signalling

Neuronal mitochondrial dysfunction causes primary mitochondrial diseases and likely contributes to neurodegenerative diseases including Parkinson's and Alzheimer's disease. Mitochondrial dysfunction has also been documented in neurodevelopmental disorders such as tuberous sclerosis complex and autism spectrum disorder. Only symptomatic treatments exist for neurodevelopmental disorders, while neurodegenerative diseases are largely untreatable. Altered mitochondrial function activates mitochondrial retrograde signalling pathways, which enable signalling to the nucleus to reprogramme nuclear gene expression. In this review, we discuss the role of mitochondrial retrograde signalling in neurological diseases. We summarize how mitochondrial dysfunction contributes to neurodegenerative disease and neurodevelopmental disorders. Mitochondrial signalling mechanisms that have relevance to neurological disease are discussed. We then describe studies documenting retrograde signalling pathways in neurons and glia, and in animal models of neuronal mitochondrial dysfunction and neurological disease. Finally, we suggest how specific retrograde signalling pathways can be targeted to develop novel treatments for neurological diseases. This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.

scholarly journals Ndufs1 Deficiency Aggravates the Mitochondrial Membrane Potential Dysfunction in Pressure Overload-Induced Myocardial Hypertrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Rongjun Zou ◽  
Jun Tao ◽  
Junxiong Qiu ◽  
Wanting Shi ◽  
Minghui Zou ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Pressure Overload ◽  
Heart Tissue ◽  
Ang Ii ◽  
Mechanistic Studies ◽  
Mitochondrial Mass ◽  
Mitochondrial Dna Content

Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH.

Novel IBA57 Mutations in Two Chinese Patients and Literature Review of Multiple Mitochondrial Dysfunction Syndrome

2021 ◽  
Author(s):  
Feixia Zhan ◽  
Xiaoli Liu ◽  
Ruilong Ni ◽  
Tiaotiao Liu ◽  
Yuwen Cao ◽  
...  
Keyword(s):  
Literature Review ◽  
Mitochondrial Dysfunction ◽  
Clinical Investigation ◽  
Brain Mri ◽  
Disease Onset ◽  
Nuclear Gene ◽  
Chinese Patients ◽  
Mitochondrial Enzymes ◽  
Clinical Genetic ◽  
Initial Symptoms

Abstract Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, and the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 mutations, one shared variant (c.286T > C) has been previously reported, the remaining two (c.189delC and c.580A > G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

scholarly journals Unanswered Questions in Friedreich Ataxia

2012 ◽  
Vol 27 (9) ◽  
pp. 1223-1229 ◽  
Author(s):  
David R. Lynch ◽  
Eric C. Deutsch ◽  
Robert B. Wilson ◽  
Gihan Tennekoon
Keyword(s):  
Clinical Trials ◽  
Mitochondrial Dysfunction ◽  
Gene Product ◽  
Friedreich Ataxia ◽  
Evidence Based ◽  
The Past ◽  
Its Gene ◽  
New Evidence

During the past 15 years, the pace of research advancement in Friedreich ataxia has been rapid. The abnormal gene has been discovered and its gene product characterized, leading to the development of new evidence-based therapies. Still, various unsettled issues remain that affect clinical trials. These include the level of frataxin deficiency needed to cause disease, the mechanism by which frataxin-deficient mitochondrial dysfunction leads to symptomatology, and the reason selected cells are most affected in Friedreich ataxia. In this review, we summarize these questions and propose testable hypotheses for their resolution.

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