Membrane-tethering of cytochrome c accelerates regulated cell death in yeast

• Published in: Cell death & disease Vol. 11; no. 9; p. 722
• Main Authors: Toth, Alexandra, Aufschnaiter, Andreas, Fedotovskaya, Olga, Dawitz, Hannah, Ädelroth, Pia, Büttner, Sabrina, Ott, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-09-2020; Springer Nature B.V
• Subjects: 13/31; 13/44; 14/19; 14/34; 45/77; 631/45/612/1240; 631/80/642/333/1465; 631/80/82; 82/1; 82/29; 82/80; Acetic acid; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase; Cell Biology; Cell Culture; Cell death; Cell Death - physiology; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Cytosol; Electron transport; Humans; Immunology; Life Sciences; Life span; Mitochondria; Mitochondria - metabolism; Oxidative phosphorylation; Oxidative stress; Oxygen consumption; Phosphorylation; Yeast; Yeasts - pathogenicity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02920-0

Intrinsic apoptosis as a modality of regulated cell death is intimately linked to permeabilization of the outer mitochondrial membrane and subsequent release of the protein cytochrome
c
into the cytosol, where it can participate in caspase activation via apoptosome formation. Interestingly, cytochrome
c
release is an ancient feature of regulated cell death even in unicellular eukaryotes that do not contain an apoptosome. Therefore, it was speculated that cytochrome
c
release might have an additional, more fundamental role for cell death signalling, because its absence from mitochondria disrupts oxidative phosphorylation. Here, we permanently anchored cytochrome
c
with a transmembrane segment to the inner mitochondrial membrane of the yeast
Saccharomyces cerevisiae
, thereby inhibiting its release from mitochondria during regulated cell death. This cytochrome
c
retains respiratory growth and correct assembly of mitochondrial respiratory chain supercomplexes. However, membrane anchoring leads to a sensitisation to acetic acid-induced cell death and increased oxidative stress, a compensatory elevation of cellular oxygen-consumption in aged cells and a decreased chronological lifespan. We therefore conclude that loss of cytochrome
c
from mitochondria during regulated cell death and the subsequent disruption of oxidative phosphorylation is not required for efficient execution of cell death in yeast, and that mobility of cytochrome
c
within the mitochondrial intermembrane space confers a fitness advantage that overcomes a potential role in regulated cell death signalling in the absence of an apoptosome.