Title:Modulating Mitophagy in Mitochondrial Disease
Volume: 25
Issue: 40
Author(s): Eszter Dombi, Heather Mortiboys and Joanna Poulton*
Affiliation:
- Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford,United Kingdom
Keywords:
Mitophagy, AICAR, metformin, Coenzyme Q10, idebenone, phenanthroline.
Abstract: Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial
DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins.
Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of
disorders that can present at any age and can affect any type of tissue.
The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional
and redundant mitochondria through a specific quality control mechanism termed mitophagy.
Mitochondria could be targeted for autophagic degradation for a variety of reasons including
basal turnover for recycling, starvation induced degradation, and degradation due to
damage. While the core autophagic machinery is highly conserved and common to most
pathways, the signaling pathways leading to the selective degradation of damaged mitochondria
are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent
on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent
of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2
mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require
PI3K.
Autophagy and mitophagy play an important role in human disease and hence could serve as
therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders.
Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin)
and may affect this by activating the AMP-activated protein kinase signaling pathways.
Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and
the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by
benefiting mitochondrial function.
