Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression.

Abstract

Activity of mitochondrial respiratory chain complexes with and without mitochondrially encoded subunits was assessed in failing human myocardium together with parameters of mitochondrial gene expression. Mutations and deletions in mitochondrial genome (mtDNA) sporadically accumulate in the aging myocardium. In experimental heart failure, they are discussed to be a generalized problem resulting in disturbances of mitochondrial gene expression and mitochondrial function. In left ventricular specimens from 43 explanted failing hearts and 10 donor hearts, enzyme activities of respiratory chain complexes, messenger ribonucleic acid (mRNA) expression of mitochondrially and nuclear encoded mitochondrial components (reverse transcriptase-polymerase chain reaction, Northern blot), undeleted wildtype mtDNA (Southern blot), and nuclear encoded mitochondrial transcription factor A (mtTFA) (Western blot) were quantified. Citrate synthase normalized activity of mitochondrial respiratory chain complex I, which contains seven mitochondrially encoded subunits, was decreased by 28% in terminally failing myocardium, whereas the activity of the exclusively nuclear encoded complex II was unchanged. However, the amount of intact mtDNA, the mRNA of all mitochondrially encoded subunits of the entire respiratory chain, the amount of mtTFA, and the enzymatic activity of complex III and complex IV, which also contain mitochondrially encoded subunits, were normal compared with donor hearts, excluding generalized disturbance of mitochondrial gene expression. Retrospective analysis of drug therapy before transplantation identified beta-blockers as one putative protection against this disturbance. In terminally failing human myocardium of patients receiving drug therapy, complex I depression is not caused by mtDNA damage and disturbed mitochondrial gene expression. The absence of mtDNA damage should facilitate recovery of the overloaded myocardium, if effective unloading could be achieved.