Mitochondrial DNA (
mtDNA) mutations are responsible for human
neuromuscular diseases caused by
mitochondrial dysfunction.
Myoclonus epilepsy associated with ragged-red fibers (
MERRF) is a maternally inherited
mitochondrial encephalomyopathy with various syndromes involving both muscular and nervous systems. The most common mutation in
MERRF syndrome, A8344G mutation in
mtDNA, has been associated with severe defects in
protein synthesis. This defect impairs assembly of complexes in electron transport chain and results in decreased respiratory function of mitochondria. In this study, we showed a significant decrease of the
heat shock protein 27 (Hsp27) in lymphoblastoid cells derived from a
MERRF patient and in cybrid cells harboring
MERRF A8344G mutation. However, normal cytoplasmic distributions of Hsp27 and normal heat shock responses were observed in both wild type and mutant cybrids. Furthermore, overexpression of wild type Hsp27 in mutant
MERRF cybrids significantly decreased cell death under
staurosporine (STS) treatment, suggesting a protective function of Hsp27 in cells harboring the A8344G mutation of
mtDNA. Meanwhile,
reverse transcriptase PCR showed no difference in the
mRNA level between normal and mutant cybrids, indicating that alterations may occur at the
protein level. Evidenced by the decreased levels of Hsp27 upon treatment with
proteasome inhibitor,
starvation and
rapamycin and the accumulation of Hsp27 upon lysosomal inhibitor treatment; Hsp27 may be degraded by the autophagic pathway. In addition, the increased formation of LC3-II and autophagosomes was found in
MERRF cybrids under the basal condition, indicating a constitutively-activated autophagic pathway. It may explain, at least partially, the faster turnover of Hsp27 in
MERRF cybrids. This study provides information for us to understand that Hsp27 is degraded through the autophagic pathway and that Hsp27 may have a protective role in
MERRF cells. Regulating Hsp27 and the autophagic pathway might help develop therapeutic solutions for treatment of
MERRF syndrome in the future.