Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy

Ariadne Vlahakis, Nerea Lopez Muniozguren, Ted Powers

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1-deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.

Original languageEnglish (US)
Pages (from-to)779-788
Number of pages10
JournalJournal of Cell Biology
Volume215
Issue number6
DOIs
StatePublished - 2016

Fingerprint

Autophagy
Calcium Channels
Respiration
Calcineurin
Amino Acids
Oxidative Stress
Phosphotransferases
Calcium
Sirolimus
Starvation
Endoplasmic Reticulum
TOR complex 2
Reactive Oxygen Species
Cell Survival
Proteins
Homeostasis
Nitrogen

ASJC Scopus subject areas

  • Cell Biology

Cite this

Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy. / Vlahakis, Ariadne; Muniozguren, Nerea Lopez; Powers, Ted.

In: Journal of Cell Biology, Vol. 215, No. 6, 2016, p. 779-788.

Research output: Contribution to journalArticle

Vlahakis, Ariadne ; Muniozguren, Nerea Lopez ; Powers, Ted. / Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy. In: Journal of Cell Biology. 2016 ; Vol. 215, No. 6. pp. 779-788.
@article{5be88edc445147e2b6d2d402858a7745,
title = "Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy",
abstract = "Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1-deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.",
author = "Ariadne Vlahakis and Muniozguren, {Nerea Lopez} and Ted Powers",
year = "2016",
doi = "10.1083/jcb.201605030",
language = "English (US)",
volume = "215",
pages = "779--788",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "6",

}

TY - JOUR

T1 - Calcium channel regulator Mid1 links TORC2-mediated changes in mitochondrial respiration to autophagy

AU - Vlahakis, Ariadne

AU - Muniozguren, Nerea Lopez

AU - Powers, Ted

PY - 2016

Y1 - 2016

N2 - Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1-deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.

AB - Autophagy is a catabolic process that recycles cytoplasmic contents and is crucial for cell survival during stress. The target of rapamycin (TOR) kinase regulates autophagy as part of two distinct protein complexes, TORC1 and TORC2. TORC1 negatively regulates autophagy according to nitrogen availability. In contrast, TORC2 functions as a positive regulator of autophagy during amino acid starvation, via its target kinase Ypk1, by repressing the activity of the calcium-dependent phosphatase calcineurin and promoting the general amino acid control (GAAC) response. Precisely how TORC2-Ypk1 signaling regulates calcineurin within this pathway remains unknown. Here we demonstrate that activation of calcineurin requires Mid1, an endoplasmic reticulum-localized calcium channel regulatory protein implicated in the oxidative stress response. We find that normal mitochondrial respiration is perturbed in TORC2-Ypk1-deficient cells, which results in the accumulation of mitochondrial-derived reactive oxygen species that signal to Mid1 to activate calcineurin, thereby inhibiting the GAAC response and autophagy. These findings describe a novel pathway involving TORC2, mitochondrial oxidative stress, and calcium homeostasis for autophagy regulation.

UR - http://www.scopus.com/inward/record.url?scp=85009168160&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009168160&partnerID=8YFLogxK

U2 - 10.1083/jcb.201605030

DO - 10.1083/jcb.201605030

M3 - Article

AN - SCOPUS:85009168160

VL - 215

SP - 779

EP - 788

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 6

ER -