The aetiology of cardiovascular disease: a role for mitochondrial DNA?

Abstract

Cardiovascular disease (CVD) is a world-wide cause of mortality in humans and its incidence is on the rise in Africa. In this review, we discuss the putative role of mitochondrial dysfunction in the aetiology of CVD and consequently identify mitochondrial DNA (mtDNA) variation as a viable genetic risk factor to be considered. We then describe the contribution and pitfalls of several current approaches used when investigating mtDNA in relation to complex disease. We also propose an alternative approach, the adjusted mutational load hypothesis, which would have greater statistical power with cohorts of moderate size, and is less likely to be affected by population stratification. We therefore address some of the shortcomings of the current haplogroup association approach. Finally, we discuss the unique challenges faced by studies done on African populations, and recommend the most viable methods to use when investigating mtDNA variation in CVD and other common complex disease.

Fig. 1

mtDNA encodes for 22 tRNA and two rRNA molecules, as well as 13 polypeptide sub-units of the OXPHOS enzyme complexes, as indicated by colour. Enzyme complexes I–IV are involved in a series of redox reactions, which transfer electrons from carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) to oxygen molecules. During these catalytically favourable reactions, H+ ions are pumped from the mitochondrial matrix into the mitochondrial intermembrane space to create a proton-motor force across the inner mitochondrial membrane. This force is used by complex V to catalyse the phosphorylation of adenosine diphosphate (ADP) to adenosine triphosphate (ATP). Complex I: NADH dehydrogenase; complex II: succinate dehydrogenase; complex III: cytochrome c reductase; complex IV: cytochrome c oxidase; complex V: ATP synthase.

Fig. 2

Mitochondrial dysfunction and mtDNA damage affect vascular health in several ways. (1) ROS aids in lesion formation by oxidising lipids, increasing the uptake of inflammatory cells into the vascular wall and enhancing proliferation and hypertrophy in VSMC. (2) During endothelium-dependant vasodilation, EC-released NO activates sGC in VSMC to produce cGMP, signalling a vasodilation response. ROS inhibits this mechanism by quenching bioavailable NO molecules. (3) Endothelial homeostasis is disturbed and plaque formation promoted when mitochondrial dysfunction leads to ROS formation and activates redox-sensitive inflammatory pathways. (4) Circulating cell-free mtDNA is similar in structure to bacterial DNA and invokes an inflammatory response, contributing to atherosclerosis. (5) Independent from ROS formation, mtDNA damage leads to aberrant ETC function and reduced ATP levels in VSMC. When cell viability is compromised, apoptosis of VSMC occurs, accelerating plaque growth and decreasing plaque integrity. (6) Through the same mechanisms, apoptosis of monocytes occurs, releasing inflammatory cytokines, contributing to inflammation and consequently, increasing plaque formation and vulnerability. ATP: adenosine triphosphate; cGMP: cyclic guanosine monophosphate; EC: endothelial cell; ETC: electron transport chain; NO: nitric oxide; ROS: reactive oxygen species; sGC: soluble guanylyl cyclase; VSMC: vascular smooth muscle cells.

Fig. 3

mtDNA morbidity map indicating clinically provenmtDNA mutations that present with syndromic or isolatedcardiac involvement. aCAR: abnormal cardiac autonomicregulation; CM: cardiomyopathy; hCM: hypertrophiccardiomyopathy; dCM: dilated cardiomyopathy;HF: heart failure; hiCM: histiocytoid cardiomyopathy;iCM: infantile cardiomyopathy; ishCM: isolated hypertrophiccardiomyopathy; LBBB: left bundle branch block;LVA: left ventricle abnormalities; LVH: left ventricularhypertrophy; LVHT: left ventricular hyper-trabeculation/non-compaction; mCM: mitochondrial cardiomyopathy;PAH: pulmonary artery hypertension; RRF: raggedred fibres; S&FCA: structural and functional cardiacabnormality; SSS: sick sinus syndrome; VD: ventriculardysfunction; VPB: ventricular premature beats; VSD:ventricular septal defect; WPW: Wolff–Parkinson–Whitesyndrome. See Table 2 for a detailed list of mutations,phenotype, references and pathogenicity scores, asdescribed in Mitchell et al. and Yarham et al.