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Mitochondrial DNA Mutations and Rheumatic Heart Diseases.

ABSTRACT: Acute rheumatic fever (ARF) is an autoimmune disease affecting the heart-valve endocardium in its final stage. Although rare in developing countries, ARF persists in third-world countries, particularly Senegal, where rheumatic heart diseases (RHDs) are the most common pediatric cardiovascular pathology. This study aimed to investigate mutations in MT-CYB in ARF and RHD in Senegalese patients. MT-CYB was amplified from blood samples from ARF patients at the Clinical of Thoracic and Cardiovascular Surgery of Fann National University Hospital Centre, Dakar, Senegal (control group, healthy individuals) and sequenced. More than half of the MT-CYB mutations (58.23%) were heteroplasmic. Transitions (61.67%) were more frequent than transversions (38.33%), and non-synonymous substitutions represented 38.33% of mutations. Unoperated RHD patients harbored frequent MT-CYB polymorphisms (7.14 ± 14.70 mutations per sample) and accounted for 72.73% of mutations. Paradoxically, subjects undergoing valvular replacement harbored infrequent polymorphisms (1.39 ± 2.97 mutations per patient) and lacked 36 mutations present in unoperated subjects. A genetic differentiation was observed between these two populations, and the mutations in operated subjects were neutral, while those in unoperated subjects were under positive selection. These results indicate a narrow link (perhaps even causal) between MT-CYB mutations and ARF and its complications (i.e., RHDs) and that these mutations are largely deleterious.

SUBMITTER: Wade FB

PROVIDER: S-EPMC6956112 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.

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Mitochondrial DNA Mutations and Rheumatic Heart Diseases.

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