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

Area of Science:

• Cellular biology
• Biochemistry
• Genetics

Background:

• The mitochondrial integrated stress response (mitoISR) is a key pathway for adapting to respiratory chain deficiencies.
• Tissue-specific regulation and adaptation of mitoISR to varying levels of mitochondrial dysfunction remain poorly understood.

Purpose of the Study:

• To investigate the role of FGF21 in the tissue-specific regulation of mitoISR.
• To understand how mitoISR adapts to different severities of mitochondrial dysfunction, particularly in cardiac tissue.

Main Methods:

• Induction of varying levels of mitochondrial cardiomyopathy.
• Analysis of mitoISR activation and FGF21 production.
• Assessment of metabolic adaptations, including one-carbon metabolism, transsulfuration, and amino acid biosynthesis, in the presence and absence of FGF21.

Main Results:

• Diverse levels of mitochondrial cardiomyopathy activate mitoISR, leading to increased FGF21 production.
• FGF21 is dispensable for severe cardiomyopathy but regulates a portion of mitoISR in mild-to-moderate cardiac OXPHOS dysfunction.
• Absence of FGF21 blunts significant metabolic adaptations, independent of ATF4.

Conclusions:

• MitoISR regulation is complex, exhibiting tissue specificity and dose dependency.
• FGF21 plays a crucial role in metabolic adaptation to mild-to-moderate mitochondrial dysfunction.
• Understanding these regulatory mechanisms is vital for addressing mitochondrial diseases.