Death by cytoplasmic accumulation

Nature, doi:10.1038/nature14859

In addition to serving as energy factories for the cell, mitochondria control cell death through different pathways. Wang and Chen now identify a distinct mechanism of mitochondria-mediated cell death, which they call mitochondrial precursor overaccumulation stress (mPOS), that arises when proteins destined for mitochondrial import accumulate in the cytoplasm, overtaxing normal cytosolic protein homeostasis (proteostasis). To do this, they first screened for yeast multicopy suppressors capable of inhibiting cell death induced by Aac2^A128P, a misfolded ATP/ADP exchanger on the mitochondrial inner membrane not directly involved in protein import. The authors found 40 genes that could suppress Aac2^A128P-induced cell degeneration when overexpressed. Of these, 32 are already known to be involved in regulating proteostasis via such systems as mRNA silencing, translation and protein turnover. The identified antidegenerative suppressors are all localized to the cytoplasm and could enhance cell viability in mutants with diverse types of mitochondrial damage affecting the inner membrane integrity and functionality. These findings led the authors to suspect that mitochondrial damage not directly in the core protein import machineries is sufficient to reduce protein import and to induce the overaccumulation of mitochondrial precursor proteins in the cytosol followed by cell death. In addition, mPOS-induced cell death can be remediated by downregulating cytosolic protein production and other proteostatic processes. The authors could detect the accumulation of both mitochondrial and nonmitochondrial proteins in the cytoplasm of AAC2^A128P cells using a proteomic approach. The accumulated nonmitochondrial proteins include Gis2—proposed to stimulate cap-independent translation—and Nog2—which inhibits nuclear export of the 60S ribosomal subunit. Although the precise mechanism remains unknown, Gis2 or Nog2 overaccumulation was shown to protect cells from mPOS-induced cell death. Overall, the study suggests a novel mechanism of mitochondria-induced cell death and identified a molecular network that protects cells from mPOS.