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Research Focus Areas:
Mitochondrial Biology & Genomics

Activation and Role of Mitochondrial Permeability Transition Pore in Excitation Contraction Coupling

Principal Investigators

W. Wang, Ph.D.


Normal cardiac function relies on highly coordinated intracellular processes, especially the timely cycling of intracellular calcium (Ca2+) and the adequate mitochondrial metabolism. To maintain high levels of energy output, cardiac mitochondria accumulate Ca2+ during cytosolic Ca2+ oscillations. However, Ca2+ overload in mitochondrial matrix causes mitochondrial permeability transition pore (mPTP) opening, a process previously regarded as the trigger of myocyte dysfunction and cause of cell death. Recently, taking advantage of a novel genetically-encoded superoxide indicator, cpYFP, we detected physiological mPTP activities coupled with bursting superoxide production, termed superoxide flash, in mitochondrial matrix of intact cardiac myocytes. Why mPTP opens under physiological conditions and what is the functional significance of mPTP activity in normal cardiac myocytes are largely unknown. Based on preliminary results, we hypothesize that physiological mPTP opening is associated with beat-to-beat Ca2+ accumulation in mitochondrial matrix and plays important regulatory roles in local Ca2+ handling through production and release of reactive oxygen species (ROS). In this proposal, the P.I. will design experiments to determine that matrix Ca2+ is the intrinsic trigger of physiological mPTP activity and superoxide flash production. Further, we will demonstrate that physiological mPTP opening modulates cardiac Ca2+ release events, named Ca2+ sparks through locally released ROS.

Mitochondrial Biology & Genomics:
Research Projects