FAK regulates cardiomyocyte mitochondrial fission and function through Drp1

Area of Science:

• Cardiovascular Biology
• Mitochondrial Dynamics
• Cell Signaling

Background:

• Loss of dynamin-related protein 1 (Drp1) in cardiomyocytes leads to energy deficits and heart failure.
• Understanding the regulation of Drp1 phosphorylation and mitochondrial function is crucial for cardiac health.

Purpose of the Study:

• To elucidate the intracellular signaling pathways and extracellular factors that control Drp1 phosphorylation, mitochondrial morphology, and function in cardiomyocytes.
• To investigate the role of focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2) in fibronectin- and mechanical stretching-induced Drp1 activation.

Main Methods:

• Neonatal rat ventricular myocytes (NRVMs) were subjected to cyclic mechanical stretching.
• Experiments involved assessing Drp1 phosphorylation, mitochondrial morphology, oxygen consumption rate, and ATP content.
• The FAK-ERK1/2-Drp1 pathway was investigated using pharmacological inhibitors and in response to fibronectin and adrenergic agonists.

Main Results:

• Cyclic mechanical stretching induced mitochondrial fission via Drp1 and FAK, with FAK regulating Drp1 phosphorylation.
• Extracellular fibronectin activated Drp1 and promoted mitochondrial fission through FAK and ERK1/2, increasing cellular oxygen consumption and ATP levels.
• Inhibition of the FAK-ERK1/2-Drp1 pathway resulted in cellular energy shortage.
• This pathway was activated by adrenergic agonists, contributing to stimulated respiration, but fibronectin limited agonist-induced respiration by restricting Drp1 phosphorylation.

Conclusions:

• Extracellular fibronectin and adrenergic stimulations converge on the FAK-ERK1/2-Drp1 pathway to modulate mitochondrial morphology and function in cardiomyocytes.
• This pathway plays a significant role in regulating cellular energy metabolism and cardiac response to stimuli.