Discriminating between cardiolipin content and cardiolipin acyl chain composition on mitochondrial inner membrane biophysical organization

Abstract

The pathogenesis of cardiovascular diseases (CVDs) is driven, in part, from impairment in myocardial energy metabolism. There is convincing evidence that myocardial metabolic abnormalities are fundamentally driven by mitochondrial dysfunction. One poorly studied mechanism of mitochondrial dysfunction involves potential defects in the biophysical organization of the inner mitochondrial membrane (IMM), which is a critical regulator of mitochondrial function and energy metabolism. Many studies show that the mitochondrial specific phospholipid cardiolipin (CL) plays a central role in maintaining the structure of the IMM and thereby protein clustering and activity. Though, in several CVDs, such as diabetic cardiomyopathy, ischemia-reperfusion injury and heart failure, CL's unique structure is considerably altered which directly diminishes CL's function within the IMM. Two key alterations of CL that directly contribute towards mitochondrial dysfunction are a loss of CL content and aberrant CL acyl chain remodeling. However, it is currently debated as to whether a loss of CL content or CL acyl chain remodeling has a greater impact on the structure-function of the IMM. Therefore in this study, we discriminate between decreased CL content versus CL acyl chain composition on key biophysical membrane properties of the IMM. The central hypothesis for this study is that a loss of CL content, rather than CL's acyl chain composition, disrupts mitochondrial inner membrane lipid organization by directly diminishing protein clustering and activity. Using an innovative biophysical approach, which relied on the construction of biomimetic and native mitochondrial membranes, we demonstrate that the biophysical organization of the IMM is highly dependent upon specific lipid-protein interactions. More specifically we demonstrate that specific membrane associated mitochondrial proteins induce the formation of proteolipid microdomains that are sensitive to both CL concentration and extreme CL acyl chain remodeling. Collectively, our results have strong implications for the ongoing debate about surrounding CL alterations and their impact on mitochondrial inner membrane biophysical organization. By providing a connection between specific CL alterations and mitochondrial inner membrane organization, and thereby function, our results ultimately offer strategies for clinically addressing pathophysiological CL abnormalities through the design of specific CL-targeting therapeutics.