Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Abstract

Mitochondrial (mt)DNA defects , both deletions and tRNA point mutations , have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles , angulated , tubular , and concentric cristae , and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques , automated DNA sequencing, restriction enzyme digestion , and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy , and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean , 43.5 ؎ 12.7 years) , 85 had ultrastructural evidence of giant organelles , with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA , and 4 missense , one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases , the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation , cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P ‫؍‬ 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P ‫؍‬ 0.0388) , whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure. (Am J Pathol 1998, 153:1501-1510)

Mitochondrial DNA Variant for Complex I Reveals a Role in Diabetic Cardiac Remodeling

“…Molecular clinical findings indicate that some forms of dilated cardiomyopathy are linked to mitochondrial mtDNA defects (29,30). The changes at the mtDNA level vary from deletions to point mutations, which generally correspond with the severity of disease.…”

Mitochondria in the human heart

“…End-stage HF was associated with multiple mitochondrial functional injuries, e.g., a decrease of ETC activities per muscle mass, most notably CI (Scheubel et al 2002), CIII (Buchwald et al 1990;Jarreta et al 2000;Marin-Garcia et al 1995), and CIV (Arbustini et al 1998;Quigley et al 2000), and a decrease in OXPHOS capacity in the presence of substrates directing electrons into CI in permeabilized fibers (Saks et al 1991;Sharov et al 2000). Part of the loss of mitochondrial ETC activity or OXPHOS per g of muscle is explainable by a decrease in mitochondrial content occurring also in endstage HF (Kalsi et al 1999;Nascimben et al 1996;Quigley et al 2000).…”

Oxidative Stress in Heart Failure: The Role of Mitochondria.

“…An accumulation of the deleted forms of mtDNAin the myocardiumfrequently results in either cardiac hypertrophy, conduction block, or HF (17). Furthermore, there is nowa consensusview that mutations in mtDNAand abnormalities in mitochondrial function are associated with commonforms of cardiac diseases such as ischemic heart disease (18) and dilated cardiomyopathy (19). In these conditions, however, the strict causal relationships between abnormalities in mtDNAand cardiac dysfunction have yet to be fully elucidated (20).…”