Mitochondrial genome variability: the effect on cellular functional activity

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Abstract

Mitochondria are the key players in cell metabolism, calcium homeostasis, and reactive oxygen species (ROS) production. Mitochondrial genome alterations are reported to be associated with numerous human disorders affecting nearly all tissues. In this review, we discuss the available information on the involvement of mitochondrial DNA (mtDNA) mutations in cell dysfunction.

Most cited references 51

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The mitochondrial genome: structure, transcription, translation and replication.

J Taanman (1999)

Mitochondria play a central role in cellular energy provision. The organelles contain their own genome with a modified genetic code. The mammalian mitochondrial genome is transmitted exclusively through the female germ line. The human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16569 bp and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 polypeptides. The mtDNA-encoded polypeptides are all subunits of enzyme complexes of the oxidative phosphorylation system. Mitochondria are not self-supporting entities but rely heavily for their functions on imported nuclear gene products. The basic mechanisms of mitochondrial gene expression have been solved. Cis-acting mtDNA sequences have been characterised by sequence comparisons, mapping studies and mutation analysis both in vitro and in patients harbouring mtDNA mutations. Characterisation of trans-acting factors has proven more difficult but several key enzymes involved in mtDNA replication, transcription and protein synthesis have now been biochemically identified and some have been cloned. These studies revealed that, although some factors may have an additional function elsewhere in the cell, most are unique to mitochondria. It is expected that cell cultures of patients with mitochondrial diseases will increasingly be used to address fundamental questions about mtDNA expression.

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Mammalian Mitochondria and Aging: An Update.

Timo E S Kauppila, Johanna H K Kauppila, Nils-Göran Larsson (2017)

Mitochondria were first postulated to contribute to aging more than 40 years ago. During the following decades, multiple lines of evidence in model organisms and humans showed that impaired mitochondrial function can contribute to age-associated disease phenotypes and aging. However, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations, there are now strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mtDNA polymerase. Currently, a substantial amount of mitochondrial research is focused on finding ways to either remove or counteract the effects of mtDNA mutations with the hope of extending the human health- and lifespan. This review summarizes the current knowledge regarding the formation of mtDNA mutations and their impact on mitochondrial function. We also critically discuss proposed pathways interlinked with mammalian mtDNA mutations and suggest future research strategies to elucidate the role of mtDNA mutations in aging.

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Mitochondrial reactive oxygen species and cancer

Lucas Sullivan, Navdeep Chandel (2014)

Mitochondria produce reactive oxygen species (mROS) as a natural by-product of electron transport chain activity. While initial studies focused on the damaging effects of reactive oxygen species, a recent paradigm shift has shown that mROS can act as signaling molecules to activate pro-growth responses. Cancer cells have long been observed to have increased production of ROS relative to normal cells, although the implications of this increase were not always clear. This is especially interesting considering cancer cells often also induce expression of antioxidant proteins. Here, we discuss how cancer-associated mutations and microenvironments can increase production of mROS, which can lead to activation of tumorigenic signaling and metabolic reprogramming. This tumorigenic signaling also increases expression of antioxidant proteins to balance the high production of ROS to maintain redox homeostasis. We also discuss how cancer-specific modifications to ROS and antioxidants may be targeted for therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Ther Clin Risk Manag

Journal ID (iso-abbrev): Ther Clin Risk Manag

Journal ID (publisher-id): Therapeutics and Clinical Risk Management

Title: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6336

ISSN (Electronic): 1178-203X

Publication date Collection: 2018

Publication date (Electronic): 09 February 2018

Volume: 14

Pages: 237-245

Affiliations

[1 ]Laboratory of Gene Therapy, Biocad Biotechnology Company, Saint-Petersburg, Strelnya, Russia

[2 ]Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Sciences, Moscow, Russia

[3 ]Federal Scientific Clinical Center for Resuscitation and Rehabilitation, Moscow, Russia

[4 ]Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia

Author notes

Correspondence: Alexander N Orekhov, Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya Street 8, Moscow 125315, Russia, Tel +7 903 169 08 66, Email a.h.opexob@ 123456gmail.com

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Publisher ID: tcrm-14-237

DOI: 10.2147/TCRM.S153895

PMC ID: 5811183

PubMed ID: 29467576

SO-VID: 29836cde-1ef6-42ae-9e7c-907adcfaaf4f

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The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Mitochondrial genome variability: the effect on cellular functional activity

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Abstract

Most cited references 51

The mitochondrial genome: structure, transcription, translation and replication.

Mammalian Mitochondria and Aging: An Update.

Mitochondrial reactive oxygen species and cancer

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