FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction

Marijana Croon (1) , Karolina Szczepanowska (1, 2) , Milica Popovic (1) , Christina Lienkamp (3) , Katharina Senft (1) , Christoph Paul Brandscheid (1) , Theresa Bock (1) , Leoni Gnatzy-Feik (1) , Artem Ashurov (1) , Richard James Acton (1) , Harshita Kaul (1) , Claire Pujol (4) , Stephan Rosenkranz (1) , Marcus Krüger (1) , Aleksandra Trifunovic (1)

1 Universität zu Köln = University of Cologne
2 PAN - Polish Academy of Sciences
3 Max planck Institute for Biology of Ageing [Cologne]
4 Biologie mitochondriale – Mitochondrial biology

The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-to-moderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.

Domains: Life Sciences [q-bio]; Santé publique et épidémiologie

Marijana Croon, Karolina Szczepanowska, Milica Popovic, Christina Lienkamp, Katharina Senft, et al.. FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction. Science Advances , 2022, 8 (14), pp.eabn7105. ⟨10.1126/sciadv.abn7105⟩. ⟨pasteur-03639915⟩