The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells

Abstract

The ability to withstand mitochondrial damage is especially critical for cells such as neurons that survive long-term. We report that cytochrome c (cyt c), a key trigger of apoptosis that is released upon mitochondrial permeabilization, is targeted for proteasome-mediated degradation in postmitotic neurons but not in normal proliferating cells. Importantly, an unbiased siRNA screen identifiedp53 associated Parkin-like cytoplasmic protein (PARC/CUL9) as an E3 ligase that targets cyt c for degradation. PARC/CUL9 levels were markedly elevated with neuronal differentiation and over expression of PARC/CUL9 was sufficient to promote cyt c degradation. Conversely, PARC/CUL9 deficiency made neurons more vulnerable to mitochondrial damage, compromising their ability to survive long-term. Degradation of cyt c by an identical mechanism was also seen in brain tumor cells, highlighting this as an important strategy engaged by neurons and cancer cells to ensure optimal long-term survival.

Mild mitochondrial metabolic deficits by α-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease

“…For example, in mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevents the proteasome-dependent degradation of cytochrome c in response to induced mitochondrial stress. P53-associated parkin-like cytoplasmic protein (PARC, also known as CUL9) is an E3 ligase that targets cytochrome c for degradation in neurons (Gama et al, 2014). Neurons are remarkably capable of maintaining MMP despite the loss of cytochrome c, in part by maintaining ATP generation through glycolysis.…”

A fate worse than death: apoptosis as an oncogenic process

“…Importantly, because MOMP often kills irrespective of caspase activity, it is considered a cellular death sentence 12 . Nevertheless, there are notable exceptions; for example some types of neurons can circumvent the lethal effect of MOMP by inhibiting caspase activity through various means including low expression of APAF-1 or degradation of cytochrome c 13,14 . Moreover, proliferating cells under caspase-inhibited conditions can also survive MOMP dependent upon glycolytic metabolism and autophagy 15 .…”

Apoptotic cell death regulation in neurons

“…In addition to inactivating the pro‐apoptotic functions of cyt c by altering its redox state, neurons can also target cytosolic cyt c for degradation . Degradation of cyt c is mediated, at least in part, by the E3 ubiquitin ligase Cul9/Parc . Interestingly, whether or not cyt c is degraded seems to be dependent on the presence and availability of its binding protein Apaf‐1.…”

“…Interestingly, whether or not cyt c is degraded seems to be dependent on the presence and availability of its binding protein Apaf‐1. While cytosolic cyt c is not degraded in wild‐type mouse embryonic fibroblasts, it is targeted for degradation in Apaf‐1‐deficient fibroblasts . Thus, the degradation of cytosolic cyt c seen in neurons could be because neurons are known to express low levels of Apaf‐1 .…”