Basic mechanisms of autophagy in neuroprotection and neurodegeneration
Final Report Abstract
Mitochondrial malfunction is emerging as a contributing factor in age-related diseases, including neurodegenerative disorders. A crucial mechanism preserving mitochondrial health is the dynamic morphological transition mediated through mitochondrial fission and fusion events. Mitochondrial fusion enables inter-mitochondrial communication, exchange of metabolites, proteins and mitochondrial DNA, while fission facilitates the separation of damaged mitochondria from the mitochondrial network. The isolated, dysfunctional mitochondria are selectively recognized and degraded by autophagy, in a process termed mitophagy. Our understanding on how damaged mitochondria are eliminated by selective-types of autophagy has dramatically increased in the recent years, but much less is known about how mitochondria are degraded during stress-induced, non-selective autophagy. Therefore, we focused on the analysis of mitochondrial degradation during starvation, a condition thought to induce bulk degradation of cytoplasmic material and whole organelles, including mitochondria. During basal autophagy, mitophagy is preceded by mitochondrial fragmentation, but the mitochondrial morphology during starvation was unknown. Surprisingly, we identified that nutrient depletion induces a rapid shift in mitochondrial shape as mitochondria fuse into large interconnected networks. Mitochondrial fusion was dependent on the type of starvation and individual depletion of one nutrient at a time identified the lack of nitrogen sources as most potent fusion-signal. However, additional depletion of serum, amino acids and glucose enhanced the process, indicating an additive effect. Next, we identified starvation-induced mitochondrial fusion to be dependent on the decrease in mitochondrial fission through modulation of two phosphorylation sites in the fission protein dynamin-related protein 1 (Drp1, Drp1S616 and Drp1S637). The decrease in Drp1-dependent fission allowed for unopposed fusion, leading to extensive mitochondrial tubulation. Finally, we establish that starvation-induced mitochondrial fusion prevents mitochondria from autophagosomal degradation and enhances cellular survival during nutrient sparse times.
Publications
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Fuse or die: Shaping mitochondrial fate during starvation. Commun Integr Biol. 2011 Nov 1;4(6):752-4
Rambold AS, Kostelecky B, Lippincott-Schwartz J
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Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle. 2011 Dec 1;10(23):4032-8
Rambold AS, Lippincott-Schwartz J
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Together we are stronger: fusion protects mitochondria from autophagsosomal degradation. Autophagy. 2011 Dec;7(12):1568-9
Rambold AS, Kostelecky B, Lippincott-Schwartz J
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Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10190-5
Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J
