IFN-γ and androgens disrupt mitochondrial function in murine myocytes

Area of Science:

• Immunology
• Cardiovascular Science
• Metabolic Research

Background:

• Chronic inflammation and autoimmune diseases are linked to fatigue and cardiovascular issues.
• Immune dysfunction may impact myocyte mitochondria, contributing to fatigue pathogenesis.
• Interferon-gamma (IFN-γ) plays a role in immune responses and metabolic regulation.

Purpose of the Study:

• To investigate the role of immune dysfunction-driven mitochondrial changes in fatigue and cardiovascular complications.
• To examine the effects of persistent low-level IFN-γ expression on myocyte mitochondria under androgen exposure.
• To elucidate the mechanisms linking autoimmunity, mitochondrial function, and stress response.

Main Methods:

• Utilized IFN-γ AU-Rich Element deletion (ARE) mice under androgen exposure.
• Assessed myocyte mitochondrial and metabolic function in male or castrated ARE mice.
• Employed echocardiography to evaluate cardiac function, specifically left ventricular ejection fraction post-stress.

Main Results:

• Persistent low-level IFN-γ expression induced mitochondrial and metabolic deficiencies in myocytes.
• Mitochondrial deficiencies correlated with reduced left ventricular ejection fraction under stress.
• Inefficiencies and structural changes in mitochondria, alongside altered gene expression, were linked to male-biased fatigue and cardiomyopathy.

Conclusions:

• Male androgen background and autoimmunity impair mitochondrial function and stress resilience.
• Pharmacological blockade of stress signaling can protect cardiac function.
• IFN-γ influences fatigue, energy metabolism, and autoimmunity through diverse mechanisms, particularly impacting mitochondrial health.