mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial~stress response (ISRmt), which is controlled by~mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.
Originalspråkengelska
TidskriftCell Metabolism
Volym26
Utgåva2
Sidor (från-till)419–428
Antal sidor10
ISSN1550-4131
DOI
StatusPublicerad - 1 aug 2017
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 1182 Biokemi, cell- och molekylärbiologi
  • 3111 Biomedicinska vetenskaper

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@article{85159e786f2f4c04a70de2f6ed903e10,
title = "mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression",
abstract = "Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial~stress response (ISRmt), which is controlled by~mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.",
keywords = "1182 Biochemistry, cell and molecular biology, INTEGRATED MITOCHONDRIAL STRESS RESPONSE, ATF4, ONE-CARBON CYCLE, FOLATE CYCLE, SERINE BIOSYNTHESIS, NUCLEOTIDE SYNTHESIS, 3111 Biomedicine, MITOCHONDRIAL DISEASE, MITOCHONDRIAL DISEASE TREATMENT, RAPAMYCIN, MITOCHONDRIAL MYOPATHY",
author = "Nahid Khan and Joni Nikkanen and Shuichi Yatsuga and Christopher Jackson and Liya Wang and Swagat Pradhan and Riikka Kivel{\"a} and Alberto Pessia and Vidya Velagapudi and Anu Suomalainen",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/j.cmet.2017.07.007",
language = "English",
volume = "26",
pages = "419–428",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",

}

mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression. / Khan, Nahid; Nikkanen, Joni; Yatsuga, Shuichi; Jackson, Christopher; Wang, Liya; Pradhan, Swagat; Kivelä, Riikka; Pessia, Alberto; Velagapudi, Vidya; Suomalainen, Anu .

I: Cell Metabolism, Vol. 26, Nr. 2, 01.08.2017, s. 419–428.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

AU - Khan, Nahid

AU - Nikkanen, Joni

AU - Yatsuga, Shuichi

AU - Jackson, Christopher

AU - Wang, Liya

AU - Pradhan, Swagat

AU - Kivelä, Riikka

AU - Pessia, Alberto

AU - Velagapudi, Vidya

AU - Suomalainen, Anu

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial~stress response (ISRmt), which is controlled by~mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.

AB - Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial~stress response (ISRmt), which is controlled by~mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.

KW - 1182 Biochemistry, cell and molecular biology

KW - INTEGRATED MITOCHONDRIAL STRESS RESPONSE

KW - ATF4

KW - ONE-CARBON CYCLE

KW - FOLATE CYCLE

KW - SERINE BIOSYNTHESIS

KW - NUCLEOTIDE SYNTHESIS

KW - 3111 Biomedicine

KW - MITOCHONDRIAL DISEASE

KW - MITOCHONDRIAL DISEASE TREATMENT

KW - RAPAMYCIN

KW - MITOCHONDRIAL MYOPATHY

UR - http://www.cell.com/cell-metabolism/abstract/S1550-4131(17)30428-X

U2 - 10.1016/j.cmet.2017.07.007

DO - 10.1016/j.cmet.2017.07.007

M3 - Article

VL - 26

SP - 419

EP - 428

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 2

ER -