A Method of Pharmacological Modulation of Mitophagy

Mitochondria are biological power plants, swarming and multiplying in their hundreds like bacteria inside every cell. They contain a little DNA, separate from that in the cell nucleus, and some forms of damage to that DNA result in cells taken over by malfunctioning mitochondria. These faulty cells increase in number over a lifetime, exporting damaged molecules far and wide in the body, and contributing to numerous aspects of degenerative aging.

Quality control mechanisms watch over mitochondria and destroy those that become damaged, a process known as mitophagy. Clearly these mechanisms are not perfect and important forms of damage slip through the net. While it is thought that increased cellular housekeeping activity, including mitophagy, is a key contributing mechanism in most of the known methods of slowing aging in mice and other species, it is unclear as to whether this can provide protection against forms of damage to mitochondia that evade mitophagy under normal circumstances. Will they still evade a more active level of mitophagy that is just a greater repetition of the same processes? In part this uncertainty is due to the lack of any methodology to spur the operation of mitophagy in isolation, so as to see what happens without the complication of numerous other changes taking place at the same time. These researchers claim development of such a means:

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent.

We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245710/


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