Mitochondrial myopathy induces a starvation-like response

Henna Tyynismaa, Christopher J. Carroll, Nuno Raimundo, Sofia Ahola-Erkkilä, Tina Wenz, Heini Ruhanen, Kilian Guse, Akseli Hemminki, Katja E. Peltola-Mjøsund, Valtteri Tulkki, Matej Orešič, Carlos T. Moraes, Kirsi Pietiläinen, Iiris Hovatta, Anu Suomalainen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

140 Citations (Scopus)

Abstract

Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.
Original languageEnglish
Pages (from-to)3948-3958
JournalHuman Molecular Genetics
Volume19
Issue number20
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

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Mitochondrial Myopathies
Starvation
Skeletal Muscle
Electron Transport
Lipid Metabolism
Mitochondrial Diseases
Metabolic Diseases
High Fat Diet
Mitochondrial DNA
Transcriptome
Adipocytes
Fasting
Fats
Hormones
Gene Expression
Amino Acids
Muscles
Mutation
Liver
Serum

Cite this

Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkilä, S., Wenz, T., Ruhanen, H., ... Suomalainen, A. (2010). Mitochondrial myopathy induces a starvation-like response. Human Molecular Genetics, 19(20), 3948-3958. https://doi.org/10.1093/hmg/ddq310
Tyynismaa, Henna ; Carroll, Christopher J. ; Raimundo, Nuno ; Ahola-Erkkilä, Sofia ; Wenz, Tina ; Ruhanen, Heini ; Guse, Kilian ; Hemminki, Akseli ; Peltola-Mjøsund, Katja E. ; Tulkki, Valtteri ; Orešič, Matej ; Moraes, Carlos T. ; Pietiläinen, Kirsi ; Hovatta, Iiris ; Suomalainen, Anu. / Mitochondrial myopathy induces a starvation-like response. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 20. pp. 3948-3958.
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title = "Mitochondrial myopathy induces a starvation-like response",
abstract = "Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.",
author = "Henna Tyynismaa and Carroll, {Christopher J.} and Nuno Raimundo and Sofia Ahola-Erkkil{\"a} and Tina Wenz and Heini Ruhanen and Kilian Guse and Akseli Hemminki and Peltola-Mj{\o}sund, {Katja E.} and Valtteri Tulkki and Matej Orešič and Moraes, {Carlos T.} and Kirsi Pietil{\"a}inen and Iiris Hovatta and Anu Suomalainen",
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Tyynismaa, H, Carroll, CJ, Raimundo, N, Ahola-Erkkilä, S, Wenz, T, Ruhanen, H, Guse, K, Hemminki, A, Peltola-Mjøsund, KE, Tulkki, V, Orešič, M, Moraes, CT, Pietiläinen, K, Hovatta, I & Suomalainen, A 2010, 'Mitochondrial myopathy induces a starvation-like response', Human Molecular Genetics, vol. 19, no. 20, pp. 3948-3958. https://doi.org/10.1093/hmg/ddq310

Mitochondrial myopathy induces a starvation-like response. / Tyynismaa, Henna; Carroll, Christopher J.; Raimundo, Nuno; Ahola-Erkkilä, Sofia; Wenz, Tina; Ruhanen, Heini; Guse, Kilian; Hemminki, Akseli; Peltola-Mjøsund, Katja E.; Tulkki, Valtteri; Orešič, Matej; Moraes, Carlos T.; Pietiläinen, Kirsi; Hovatta, Iiris; Suomalainen, Anu (Corresponding Author).

In: Human Molecular Genetics, Vol. 19, No. 20, 2010, p. 3948-3958.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Mitochondrial myopathy induces a starvation-like response

AU - Tyynismaa, Henna

AU - Carroll, Christopher J.

AU - Raimundo, Nuno

AU - Ahola-Erkkilä, Sofia

AU - Wenz, Tina

AU - Ruhanen, Heini

AU - Guse, Kilian

AU - Hemminki, Akseli

AU - Peltola-Mjøsund, Katja E.

AU - Tulkki, Valtteri

AU - Orešič, Matej

AU - Moraes, Carlos T.

AU - Pietiläinen, Kirsi

AU - Hovatta, Iiris

AU - Suomalainen, Anu

PY - 2010

Y1 - 2010

N2 - Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.

AB - Mitochondrial respiratory chain (RC) deficiency is among the most common causes of inherited metabolic disease, but its physiological consequences are poorly characterized. We studied the skeletal muscle gene expression profiles of mice with late-onset mitochondrial myopathy. These animals express a dominant patient mutation in the mitochondrial replicative helicase Twinkle, leading to accumulation of multiple mtDNA deletions and progressive subtle RC deficiency in the skeletal muscle. The global gene expression pattern of the mouse skeletal muscle showed induction of pathways involved in amino acid starvation response and activation of Akt signaling. Furthermore, the muscle showed induction of a fasting-related hormone, fibroblast growth factor 21 (Fgf21). This secreted regulator of lipid metabolism was also elevated in the mouse serum, and the animals showed widespread changes in their lipid metabolism: small adipocyte size, low fat content in the liver and resistance to high-fat diet. We propose that RC deficiency induces a mitochondrial stress response, with local and global changes mimicking starvation, in a normal nutritional state. These results may have important implications for understanding the metabolic consequences of mitochondrial myopathies.

U2 - 10.1093/hmg/ddq310

DO - 10.1093/hmg/ddq310

M3 - Article

VL - 19

SP - 3948

EP - 3958

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 20

ER -

Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T, Ruhanen H et al. Mitochondrial myopathy induces a starvation-like response. Human Molecular Genetics. 2010;19(20):3948-3958. https://doi.org/10.1093/hmg/ddq310