Mitochondrial DNA mutations and cardiovascular disease

Abstract

Purpose of Review Cardiovascular disease (CVD) is responsible for more morbidity and mortality worldwide than any other ailment. Strategies for reducing CVD prevalence must involve identification of individuals at high risk for these diseases, and the prevention of its initial development. Such preventative efforts are currently limited by an incomplete understanding of the genetic determinants of CVD risk. In this review, evidence for the involvement of inherited mitochondrial mutations in development of CVD is examined. Recent Findings Several forms of CVD have been documented in the presence of pathogenic mitochondrial DNA (mtDNA) mutations, both in isolation and as part of larger syndromes. Other “natural” mtDNA polymorphisms not overtly tied to any pathology have also been associated with alterations in mitochondrial function and individual risk for CVD, but until very recently these studies have been merely correlative. Fortunately, novel animal models are now allowing investigators to define a causal relationship between inherited “natural” mtDNA polymorphisms, and cardiovascular function and pathology. Summary Cardiovascular involvement is highly prevalent among patients with pathogenic mtDNA mutations. The relationship between CVD susceptibility and “natural” mitochondrial DNA polymorphisms requires further investigation, but will be aided in the near future by several novel experimental models.

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: Evaluation of outcomes after liver transplantation

“…Although PH can be caused by chronic liver disease and portal hypertension, PH after LT is infrequent; PH has also been reported in patients with primary mitochondrial diseases (e.g. m.3243A>G, NFU1, BOLA3) 38,39 , though the mechanism underlying this remains unknown. In addition to the two patients who initially presented with HCC in this study, three MPV17-deficient patients developed HCC 27,35,37 .…”

Mitochondrial DNA variation in sudden cardiac death: a population-based study

“…Mitochondrial diseases are common inherited neurological disorders, in which cardiac manifestations are among the core features [5,28]. The incidence of major adverse cardiac events has been reported to be increased especially among patients harbouring the m.3243A > G mutation or a single mtDNA deletion [29].…”

“…Mitochondrial diseases can manifest as cardiomyopathy, conduction defects and even SCD [5]. The m.3243A > G point mutation in the MT-TL1 gene is the most common pathogenic mtDNA mutation and causes variable clinical manifestations [6].…”

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…Furthermore, crossing MNX mice with mice over-expressing the HER2/Neu oncogene, we observed driver-dependent alterations in tumorigenesis and metastasis [62]. While not the focus of this review per se , MNX mice have uncovered existence of mtDNA modifier loci in cardiovascular disease [61], atherosclerosis [61,64], and obesity [63], strongly supporting a closer look at mitochondrial quantitative trait loci [65,66]. Early studies to dissect the molecular mechanisms identified significant and, importantly, selective changes in the methylation patterns and gene expression profiles of wild-type and MNX mice [63].…”