Mitochondrial Dynamics

Mitochondria are the sites of oxygen respiration and energy production. More than just the “powerhouse of the cell,” they also mediate lipid metabolism, cytosolic calcium buffering, apoptosis, and necrosis. They are incredibly dynamic organelles that undergo fission, fusion, intracellular motility (transport), and multiple forms of quality control. Although mitochondria possess their own genome, most of the proteins that reside in mitochondria are encoded by the nuclear genome and must be imported across the double membrane structure of the mitochondria. Dysfunctional mitochondria play a role in multiple human diseases, including ischemic stroke, Parkinson’s Disease, Alzheimer’s Disease, ALS, Leigh Syndrome, optic atrophy, and cancer. Understanding how mitochondria function and are regulated in important for the development of new therapeutic approaches for treating these diseases.

Questions About Mitochondrial Dynamics

What mediates mitochondrial motility in complex cells like neurons?

How and why do mitochondria undergo fission and fusion?

How are nuclear-encoded proteins imported into mitochondria?

How are these mitochondrial dynamics regulated?

Page Components

The p38 MAP kinase pathway modulates the hypoxia response and glutamate receptor trafficking in aging neurons.

Park EC, Rongo C. Elife. 2016 Jan 5;5. pii: e12010. doi: 10.7554/eLife.12010. PMID:26731517

Neurons are sensitive to low oxygen (hypoxia) and employ a conserved pathway to combat its effects. Here, we show that p38 MAP Kinase (MAPK) modulates this hypoxia response pathway in C. elegans. Mutants lacking p38 MAPK components pmk-1 or sek-1 resemble mutants lacking the hypoxia response component and prolyl hydroxylase egl-9, with impaired subcellular localization of Mint orthologue LIN-10, internalization of glutamate receptor GLR-1, and depression of GLR-1-mediated behaviors. Loss of p38 MAPK impairs EGL-9 protein localization in neurons and activates the hypoxia-inducible transcription factor HIF-1, suggesting that p38 MAPK inhibits the hypoxia response pathway through EGL-9. As animals age, p38 MAPK levels decrease, resulting in GLR-1 internalization; this age-dependent downregulation can be prevented through either p38 MAPK overexpression or removal of CDK-5, an antagonizing kinase. Our findings demonstrate that p38 MAPK inhibits the hypoxia response pathway and determines how aging neurons respond to hypoxia through a novel mechanism.

Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism.

Park EC, Ghose P, Shao Z, Ye Q, Kang L, Xu XZ, Powell-Coffman JA, Rongo C. EMBO J. 2012 Mar 21;31(6):1379-93. doi: 10.1038/emboj.2011.499. Epub 2012 Jan 17. Erratum in: EMBO J. 2012 Mar 21;31(6):1618-9. PMID:22252129

Oxygen influences behaviour in many organisms, with low levels (hypoxia) having devastating consequences for neuron survival. How neurons respond physiologically to counter the effects of hypoxia is not fully understood. Here, we show that hypoxia regulates the trafficking of the glutamate receptor GLR-1 in C. elegans neurons. Either hypoxia or mutations in egl-9, a prolyl hydroxylase cellular oxygen sensor, result in the internalization of GLR-1, the reduction of glutamate-activated currents, and the depression of GLR-1-mediated behaviours. Surprisingly, hypoxia-inducible factor (HIF)-1, the canonical substrate of EGL-9, is not required for this effect. Instead, EGL-9 interacts with the Mint orthologue LIN-10, a mediator of GLR-1 membrane recycling, to promote LIN-10 subcellular localization in an oxygen-dependent manner. The observed effects of hypoxia and egl-9 mutations require the activity of the proline-directed CDK-5 kinase and the CDK-5 phosphorylation sites on LIN-10, suggesting that EGL-9 and CDK-5 compete in an oxygen-dependent manner to regulate LIN-10 activity and thus GLR-1 trafficking. Our findings demonstrate a novel mechanism by which neurons sense and respond to hypoxia.