Apoptosis in mitochondrial myopathies is linked to mitochondrial proliferation

Abstract

Increased susceptibility to apoptosis has been shown in many models of mitochondrial defects but its relevance to human diseases is still discussed. We addressed the presence of apoptosis in muscle from patients with mitochondrial DNA (mtDNA) disorders. Taking advantage of the mosaic pattern of muscle morphological anomalies associated with heteroplasmic mtDNA alterations, we have used an in situ approach to address the relationship between apoptosis and respiratory defect, mitochondrial proliferation and mutation load. Different patterns of mitochondrial morphological alterations were provided by the analysis of muscles with large mtDNA deletion (16 cases) or with the MELAS mutation (4 cases). The patient's age at biopsy ranged from 0.4 to 66 years and the muscle mutant mtDNA proportion from 32 to 82%. Apoptotic muscle fibres were observed in a small proportion of muscle fibres of 16 out of the 20 biopsies by three different detection methods for different steps of apoptosis: caspase 3 activation, fragmentation of nuclear DNA [terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay] or overexpression of the pro-apoptotic factor Bax. Analysis of apoptotic features in parallel to cytochrome c oxidase (COX) and succinate dehydrogenase activity of more than 34,000 individual muscle fibres showed that apoptosis occurred only in muscle fibres with mitochondrial proliferation (ragged red fibres, RRF) irrespective of their COX activity. Molecular analyses of single muscle fibres evidenced that, as expected, the presence of COX defect was associated with higher proportion of mutant mtDNA and lower amount of normal mtDNA. Within COX-defective fibres, the presence of mitochondrial proliferation was associated with increase of the mtDNA content but without change in the ratio between normal and mutant mtDNA molecules, thus showing that mitochondrial proliferation was accompanied by similar amplification of normal and mutant mtDNA molecules. Within RRF, apoptosis was associated with higher mutation proportion, suggesting that it was provoked by severe respiratory defect in the same time as increased mitochondrial mass. In conclusion, apoptosis most probably contributes to mitochondrial pathology. It is tightly linked to mitochondrial proliferation and high mutation load. When considering training therapeutics, one will have to take into account the possibility to induce apoptosis in parallel to mitochondrial proliferation.

Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: Altered energetic efficiency?

“…Previous studies have shown mitochondrial defects associated with the development of myopathies [16,17]. The results presented here agree with those that link apoptosis with higher mutation rate in mitochondrial genes and an increased mitochondrial mass in human myopathies that are associated with intolerance to exercise, defects in the energy production and muscle weakness [18].…”

Mitochondrial DNA Content, an Inaccurate Biomarker of Mitochondrial Alteration in Human Immunodeficiency Virus-Related Lipodystrophy

“…Despite the preservation of the levels of COX activity, the altered ratio between MT-CO2p and COX4p implied that some COX complexes had an abnormal composition, thus provoking focal respiratory defects. In addition, mitochondrial proliferation has been demonstrated to be an essential factor for the induction of apoptosis in mitochondrial myopathy (1). The amount of the activated form of caspase 3, a hallmark of the cellular commitment to apoptosis (8), was therefore assessed with ELISA and found to be significantly increased in the patients' samples (median, 156% of control value, versus 110% in control samples; P ϭ 0.02) (Fig.…”

“…Despite global compensation at the tissue level, altered mitochondrial composition and increased mitochondrial mass were associated with mitochondrion-borne deleterious mechanisms, such as oxidative stress and apoptosis (1). Indeed, the expression of DDIT3, a transcription factor induced by mitochondrial reactive oxygen species (6), was increased in patients' samples.…”

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…Clinically, many researchers tried to clarify the correlation between apoptosis-related cell death and pathogenic mechanism involved in the defects in muscle and brain of patients with mitochondrial encephalomyopathies. Many well-documented studies have revealed that apoptosis is involved in the progression of muscle myopathy (Aure et al, 2006;Umaki et al, 2002). Studies showed significant signs of apoptosis in the COX-negative muscle fibers in muscle biopsies from patients who harbored high proportions of specific point mutations in tRNA genes of mtDNA.…”