Recombination of mitochondrial DNA in skeletal muscle of individuals with multiple mitochondrial DNA heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

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The generation of transplasmic Drosophila simulans by cytoplasmic injection Effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy

MGG Molecular & General Genetics ◽

10.1007/bf00260866 ◽

1989 ◽

Vol 220 (1) ◽

pp. 127-132 ◽

Cited By ~ 31

Author(s):

Eric de Stordeur ◽

Michel Solignac ◽

Monique Monnerot ◽

Jean-Claude Mounolou

Keyword(s):

Mitochondrial Dna ◽

Drosophila Simulans ◽

Mitochondrial Dna Heteroplasmy ◽

Cytoplasmic Injection

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Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome

Human Molecular Genetics ◽

10.1093/hmg/4.4.751 ◽

1995 ◽

Vol 4 (4) ◽

pp. 751-754 ◽

Cited By ~ 26

Author(s):

Chunfang Zhang ◽

Alessandra Baumer ◽

Ian R. Mackay ◽

Anthony W. Linnane ◽

Phillip Nagley

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Unusual Pattern ◽

Adult Human ◽

Fatigue Syndrome ◽

Dna Deletions

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Results of a collaborative study of the EDNAP group regarding mitochondrial DNA heteroplasmy and segregation in hair shafts

Forensic Science International ◽

10.1016/s0379-0738(03)00181-6 ◽

2004 ◽

Vol 140 (1) ◽

pp. 1-11 ◽

Cited By ~ 53

Author(s):

G Tully ◽

S.M Barritt ◽

K Bender ◽

E Brignon ◽

C Capelli ◽

...

Keyword(s):

Mitochondrial Dna ◽

Collaborative Study ◽

Mitochondrial Dna Heteroplasmy ◽

Hair Shafts

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Influence of acclimation temperature on mitochondrial DNA, RNA, and enzymes in skeletal muscle

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.3.r905 ◽

1998 ◽

Vol 275 (3) ◽

pp. R905-R912 ◽

Cited By ~ 23

Author(s):

Brendan James Battersby ◽

Christopher D. Moyes

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Steady State ◽

Muscle Fiber ◽

Copy Number ◽

White Muscle ◽

Fiber Types ◽

Mitochondrial Enzymes ◽

Dna Copy Number ◽

Mitochondrial Content

Skeletal muscle fibers typically undergo modifications in their mitochondrial content, concomitant with alterations in oxidative metabolism that occur during the development of muscle fiber and in response to physiological stimuli. We examined how cold acclimation affects the mitochondrial properties of two fish skeletal muscle fiber types and how the regulators of mitochondrial content differed between tissues. After 2 mo of acclimation to either 4 or 18°C, mitochondrial enzyme activities in both red and white muscle were higher in cold-acclimated fish. No significant differences were detected between acclimation temperatures in the abundance of steady-state mitochondrial mRNA (cytochrome- c oxidase 1, subunit 6 of F0F1-ATPase), rRNA (16S), or DNA copy number. Steady-state mRNA for nuclear-encoded respiratory (adenine nucleotide translocase 1) and glycolytic genes showed high interindividual variability, particularly in the cold-acclimated fish. Although mitochondrial enzymes were 10-fold different between the two muscle types, mitochondrial DNA copy number differed only 4-fold. The relative abundance of mitochondrial mRNA and nuclear mRNA in red and white muscle reflected the differences in copy number of their respective genes. These data suggest that the response to physiological stimuli and determination of tissue-specific mitochondrial properties likely result from the regulation of nuclear-encoded genes.

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Biased nicking of mitochondrial DNA during extraction can be avoided by choice of isolation method

10.1101/2021.02.10.430587 ◽

2021 ◽

Author(s):

Bruno Marçal Repolês ◽

Choco Michael Gorospe ◽

Phong Tran ◽

Anna Karin Nilsson ◽

Paulina H. Wanrooij

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Dna Isolation ◽

Isolation Procedure ◽

Isolation Method ◽

Strand Breaks ◽

Careful Choice ◽

Isolation Methods ◽

Solid Tissues ◽

Long Range Pcr

AbstractThe integrity of mitochondrial DNA (mtDNA) isolated from solid tissues is critical for analyses such as long-range PCR. We show that a commonly-used DNA isolation procedure preferentially introduces strand breaks into the mtDNA extracted from the skeletal muscle of aged mice, while mtDNA from adult animals is less affected. We present a comparison of mtDNA isolation methods and identify one that avoids this biased loss of muscle mtDNA integrity. Our results highlight the importance of a careful choice of mtDNA isolation method and serve as a resource to researchers planning analysis of mtDNA isolated from solid tissues.

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Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency

BMC Molecular and Cell Biology ◽

10.1186/s12860-020-00272-3 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Liya Wang ◽

Ren Sun ◽

Staffan Eriksson

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Biochemical Characterization ◽

Basic Knowledge ◽

Rat Tissues ◽

Nucleotide Synthesis ◽

Tissue Specific ◽

Mtdna Depletion ◽

Adult Rat ◽

Mitochondrial Dna Depletion

Abstract Background Deficiency in thymidine kinase 2 (TK2) or p53 inducible ribonucleotide reductase small subunit (p53R2) is associated with tissue specific mitochondrial DNA (mtDNA) depletion. To understand the mechanisms of the tissue specific mtDNA depletion we systematically studied key enzymes in dTMP synthesis in mitochondrial and cytosolic extracts prepared from adult rat tissues. Results In addition to mitochondrial TK2 a cytosolic isoform of TK2 was characterized, which showed similar substrate specificity to the mitochondrial TK2. Total TK activity was highest in spleen and lowest in skeletal muscle. Thymidylate synthase (TS) was detected in cytosols and its activity was high in spleen but low in other tissues. TS protein levels were high in heart, brain and skeletal muscle, which deviated from TS activity levels. The p53R2 proteins were at similar levels in all tissues except liver where it was ~ 6-fold lower. Our results strongly indicate that mitochondria in most tissues are capable of producing enough dTTP for mtDNA replication via mitochondrial TK2, but skeletal muscle mitochondria do not and are most likely dependent on both the salvage and de novo synthesis pathways. Conclusion These results provide important information concerning mechanisms for the tissue dependent variation of dTTP synthesis and explained why deficiency in TK2 or p53R2 leads to skeletal muscle dysfunctions. Furthermore, the presence of a putative cytosolic TK2-like enzyme may provide basic knowledge for the understanding of deoxynucleoside-based therapy for mitochondrial disorders.

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