scholarly journals Pathogenic Mitochondria DNA Mutations: Current Detection Tools and Interventions

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 192 ◽  
Author(s):  
Mohd Fazirul Mustafa ◽  
Sharida Fakurazi ◽  
Maizaton Atmadini Abdullah ◽  
Sandra Maniam
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Mitochondrial Disease ◽  
Current Knowledge ◽  
Genetic Changes ◽  
Dna Mutations ◽  
Diagnostic Technology ◽  
Mitochondria Dna ◽  
The Common ◽  
Current Detection

Mitochondria are best known for their role in energy production, and they are the only mammalian organelles that contain their own genomes. The mitochondrial genome mutation rate is reported to be 10–17 times higher compared to nuclear genomes as a result of oxidative damage caused by reactive oxygen species during oxidative phosphorylation. Pathogenic mitochondrial DNA mutations result in mitochondrial DNA disorders, which are among the most common inherited human diseases. Interventions of mitochondrial DNA disorders involve either the transfer of viable isolated mitochondria to recipient cells or genetically modifying the mitochondrial genome to improve therapeutic outcome. This review outlines the common mitochondrial DNA disorders and the key advances in the past decade necessary to improve the current knowledge on mitochondrial disease intervention. Although it is now 31 years since the first description of patients with pathogenic mitochondrial DNA was reported, the treatment for mitochondrial disease is often inadequate and mostly palliative. Advancements in diagnostic technology improved the molecular diagnosis of previously unresolved cases, and they provide new insight into the pathogenesis and genetic changes in mitochondrial DNA diseases.

Mitochondrial cardiovascular diseases

2020 ◽  
pp. 325-342
Author(s):  
Perry Elliott ◽  
Pier D. Lambiase ◽  
Dhavendra Kumar
Keyword(s):  
Mitochondrial Dna ◽  
Hypertrophic Cardiomyopathy ◽  
Cardiovascular Diseases ◽  
Mitochondrial Genome ◽  
Mitochondrial Disease ◽  
Clinical Management ◽  
Cardiac Involvement ◽  
Mitochondrial Disorders ◽  
Barth Syndrome

This chapter begins by defining the mitochondrial genome, and the subsequent assessment of suspected mitochondrial DNA (mtDNA) disorders. The incidence and prevalence of cardiac involvement in mitochondrial disorders is covered, including the probably under-reporting of this. Different cardiovascular phenotypes associated with mitochondrial disease (arrhythmias, hypertrophic cardiomyopathy, Barth syndrome etc.) are all described, and then the clinical management of the diseases are explained. As there is no fixed treatment, pharmacological regimens to avoid, and other approaches are also included.

scholarly journals Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 65 ◽  
Author(s):  
Dar-Shong Lin ◽  
Yu-Wen Huang ◽  
Che-Sheng Ho ◽  
Pi-Lien Hung ◽  
Mei-Hsin Hsu ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cell Viability ◽  
Mitochondrial Disease ◽  
Cell Model ◽  
Ips Cells ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation ◽  
Dna Mutations ◽  
Cell Death Pathway ◽  
Induced Pluripotent

Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease.

Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?

The Lancet ◽  
2002 ◽  
Vol 360 (9342) ◽  
pp. 1323-1325 ◽  
Author(s):  
Patrick F Chinnery ◽  
David C Samuels ◽  
Joanna Elson ◽  
Douglass M Turnbull
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Disease ◽  
Common Mechanism ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations

scholarly journals The Role of the Mitochondrial Genome in Ageing and Carcinogenesis

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Anna M. Czarnecka ◽  
Ewa Bartnik
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Cancer Cells ◽  
Successful Aging ◽  
Mitochondrial Haplogroups ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations

Mitochondrial DNA mutations and polymorphisms have been the focus of intensive investigations for well over a decade in an attempt to understand how they affect fundamental processes such as cancer and aging. Initial interest in mutations occurring in mitochondrial DNA of cancer cells diminished when most were found to be the same mutations which occurred during the evolution of human mitochondrial haplogroups. However, increasingly correlations are being found between various mitochondrial haplogroups and susceptibility to cancer or diseases in some cases and successful aging in others.

Mutations of the mitochondrial genome: clinical overview and possible pathophysiology of cell damage

1999 ◽  
Vol 66 ◽  
pp. 111-122 ◽  
Author(s):  
Steven M. Rothman
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Cell Damage ◽  
Genetic Research ◽  
Cellular Mechanisms ◽  
Cultured Fibroblasts ◽  
Dna Mutations ◽  
Physiological Abnormalities ◽  
Nuclear Mutations

Mitochondria possess their own DNA and transcription and translation machinery for the synthesis of 13 protein subunits for the oxidative phosphorylation system, two rRNAs and 22 tRNAs. In 1988 the first human neurodegenerative diseases associated with mutations in the mitochondrial genome were described. The most recent biochemical and genetic research suggests that mitochondrial disorders are best categorized as: (i) primary mutations of the mitochondrial DNA, either sporadic or maternally inherited; (ii) nuclear mutations that result in alterations in mitochondrial DNA or intergenomic signalling defects; or (iii) Mendelian defects that affect the respiratory chain in the absence of mitochondrial DNA mutations. There is still little information about the pathophysiology of these different disorders. In order to obtain some insight into the cellular mechanisms of neurodegeneration, we examined cultured fibroblasts from patients with the MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome, which is most frequently caused by a mutation in the mitochondrial tRNA for leucine. We found that their basal level of ionized calcium was elevated and that they could not normally sequester calcium influxes induced by depolarization. In addition, they were unable to maintain normal mitochondrial membrane potentials, as determined using a voltage-sensitive fluorescent indicator. Despite these physiological perturbations, the MELAS fibroblasts had normal concentrations of ATP. If neurons in MELAS patients have similar physiological abnormalities, their functional properties and long-term viability may be compromised.

Neurodegenerative Diseases Associated with Mitochondrial DNA Mutations

2020 ◽  
Vol 26 (1) ◽  
pp. 103-109 ◽  
Author(s):  
Olga A. Zhunina ◽  
Nikita G. Yabbarov ◽  
Andrey V. Grechko ◽  
Shaw-Fang Yet ◽  
Igor A. Sobenin ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Leigh Syndrome ◽  
Progressive External Ophthalmoplegia ◽  
Special Focus ◽  
Mtdna Mutations ◽  
Dna Mutations ◽  
Alzheimer’S Diseases ◽  
Alzheimer's Diseases

Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer’s diseases. In this review, current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson’s and Alzheimer’s diseases has been discussed.

scholarly journals Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease

2015 ◽  
Vol 77 (5) ◽  
pp. 753-759 ◽  
Author(s):  
Gráinne S. Gorman ◽  
Andrew M. Schaefer ◽  
Yi Ng ◽  
Nicholas Gomez ◽  
Emma L. Blakely ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Disease ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations
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