Mitophagy And Mitochondrial Quality Control

Mitochondria are essential for cells that need to maximize ATP production. Neurons in the brain are particularly reliant on mitochondria for their energy needs, which are tremendous due to ATP required to maintain the electrochemical membrane potential that mediates neuronal communication. Yet, mitochondria are a potential threat to cells, as they produce free radicals and reactive oxygen species as byproduct of oxidative phosphorylation. The resulting oxidative stress can damage cell and result in neurodegeneration. Unlike many cells of the body, neurons are not easily replaced by stem cells and must survive with the risk of mitochondrial oxidative stress for decades. Neurons and other cells employ quality control mechanisms to offset potential damage from rogue mitochondria. One such mechanism is mitochondria-selective autophagy (mitophagy), which recognizes rogue mitochondria, engulfs them in augophagosomal membranes, and digests them following fusion with lysosomes. Failure to remove offensive mitochondria is associated with aspects of aging and diseases like Parkinson’s Disease.

Questions About Mitophagy

How do cells recognize a rogue mitochondria from a functional one?

What are the factors that mediate mitophagy?

How does mitophagy differ in different tissue types or during aging?

How is mitophagy regulated?

What is the link between mitophagy and neurodegeneration?

Page Components

Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1/Nrf, and stomatin-like protein STL-1/SLP-2.

Ghose P, Park EC, Tabakin A, Salazar-Vasquez N, Rongo C. PLoS Genet. 2013;9(12):e1004063. doi: 10.1371/journal.pgen.1004063. Epub 2013 Dec 26. PMID: 24385935

Many aerobic organisms encounter oxygen-deprived environments and thus must have adaptive mechanisms to survive such stress. It is important to understand how mitochondria respond to oxygen deprivation given the critical role they play in using oxygen to generate cellular energy. Here we examine mitochondrial stress response in C. elegans, which adapt to extreme oxygen deprivation (anoxia, less than 0.1% oxygen) by entering into a reversible suspended animation state of locomotory arrest. We show that neuronal mitochondria undergo DRP-1-dependent fission in response to anoxia and undergo refusion upon reoxygenation. The hypoxia response pathway, including EGL-9 and HIF-1, is not required for anoxia-induced fission, but does regulate mitochondrial reconstitution during reoxygenation. Mutants for egl-9 exhibit a rapid refusion of mitochondria and a rapid behavioral recovery from suspended animation during reoxygenation; both phenotypes require HIF-1. Mitochondria are significantly larger in egl-9 mutants after reoxygenation, a phenotype similar to stress-induced mitochondria hyperfusion (SIMH). Anoxia results in mitochondrial oxidative stress, and the oxidative response factor SKN-1/Nrf is required for both rapid mitochondrial refusion and rapid behavioral recovery during reoxygenation. In response to anoxia, SKN-1 promotes the expression of the mitochondrial resident protein Stomatin-like 1 (STL-1), which helps facilitate mitochondrial dynamics following anoxia. Our results suggest the existence of a conserved anoxic stress response involving changes in mitochondrial fission and fusion.

Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system.

Toth ML, Melentijevic I, Shah L, Bhatia A, Lu K, Talwar A, Naji H, Ibanez-Ventoso C, Ghose P, Jevince A, Xue J, Herndon LA, Bhanot G, Rongo C, Hall DH, Driscoll M. J Neurosci. 2012 Jun 27;32(26):8778-90. doi: 10.1523/JNEUROSCI.1494-11.2012. PMID: 22745480

Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: (1) accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies.