Mitophagy and neurodegeneration

Mitochondria, known as the "powerhouse of the cell," are the principal sites of adenosine triphosphate (ATP) production in aerobic, nonphotosynthetic eukaryotic cells. Most classical textbooks depict these double membrane–bound organelles as solitary and static structures. However, we now know that mitochondria are complex, dynamic, and mobile organelles that constantly undergo membrane remodeling through repeated cycles of fusion and fission, as well as regulated turnover. Collectively, these varied processes help maintain the quality, and thereby the optimal function of mitochondria, as well as allow the organelle to respond rapidly to changes in cellular energy status. The dynamic nature of mitochondria is particularly important for neuronal function, whose unique demands for energy require a highly adaptable mitochondrial network to support. The high energy demand of neurons is critical for several bioenergetically expensive neuronal processes that include axonal transport of macromolecules and organelles 176(including mitochondria) toward distally located synaptic terminals, maintenance of membrane potential, neurotransmitters uptake and release, and buffering of cytosolic calcium (Schwarz 2013). Among these, perhaps the need for active transportation of components over large distances is one that best distinguishes neurons from their nonneuronal counterparts and arguably also the most fascinating feature about these polarized cells. Although the dimensions of the majority of cells in our body are in the micrometers range, neurons can extend their processes (especially the axon) for much longer distances. For example, the axonal length of a motor neuron in humans is about 1 m. In blue whales, spinal tracts can reach an unimaginable 30 m length (Durcan et al. 2014)! Even when confined to the human brain, the axonal length of projection neurons such as the substantia nigra dopaminergic neurons, including its arborization, can be as long as 0.5 m, and each axon in turn can support nearly 400,000 synapses (Matsuda et al. 2009). The maintenance of an active transport system to supply energy to distally located synapses presents an exquisite challenge to neurons. Furthermore, synapses are themselves metabolically extremely demanding. With every synaptic vesicle release, tens of millions of ions will enter the postsynaptic side as a result of the opening of ion channels. To return the postsynaptic activated neuron to the basal state, one could imagine the large number of ATP that needs to be hydrolyzed to transport the influxed ions out to the extracellular space. The same scenario happens with every action potential fired as the neuronal membrane restores itself back to the resting potential. Notwithstanding this, it is perhaps still amazing to note from a recent imaging study that a single cortical neuron consumes nearly 5 billion ATP per second (Zhu et al. 2012)! One could therefore readily appreciate the urgency for neurons to maintain a constant pool of bioenergetically competent mitochondria that are appropriately distributed to all regions of the cell and to organize these organelles into a dynamic network that could respond rapidly to the changing landscape of neuronal ATP needs. As mentioned above, the remodeling of mitochondrial network also includes its turnover. This is particularly important for postmitotic neurons that need to survive through the entire lifespan of an organism. Comparatively, the lifespan of injured mitochondria is much shortened. Hence, timely removal of these damaged mitochondria is of utmost importance to maintain healthy mitochondrial network to support neuronal survival. The constant turnover of old and/or dysfunctional mitochondria is achieved by a regulated process known as "mitophagy." Significant insights have been obtained in the last decade or so regarding the process of intracellular mitochondrial clearance. However, much of what we know about the mechanisms underlying mitophagy is gleaned from studies in nonneuronal cells that are usually conducted in the presence of chel uncouplers such as carbonyl cyanide m-chlorophenylhydrazone (CCCP). These chemicals serve to collapse the mitochondrial membrane potential (ΔΨm), typically at a concentration that is generally regarded as nonphysiological. Nonetheless, the information obtained has been useful in guiding researchers toward the elucidation of a similar mechanism underlying mitophagy in neurons. In the following sections, we will provide a brief overview of the mechanisms underlying mitophagy and an update on the current understandings of the process in neurons along with its potential role in neurodegeneration.

Duke Scholars

Author Tso-Pang Yao Pharmacology & Cancer Biology