Mechanistic visualization of pathophysiological regulation of cardiolipin in mitochondria

Mitochondrion, in addition to provide energy for cell, potentially arbitrates apoptosis. Elevated mitochondrial reactive oxygen species (mROS) and mitochondrial Ca2+ (mCa2+) and depolarized mitochondrial membrane potential (△Ψm) together with enhanced fissed mitochondria, trigger the mitochondrial permeability transition (MPT) for lethal proteins release to cultivate final apoptosis. Recently, cardiolipin (CL), an inner mitochondrial component, has been identified as a signature phospholipid that is crucial for a diverse range of mitochondrial activities in addition to ATP production. Alterations in cardiolipin content or composition are associated with pathological conditions and diseases including neurodegeneration and aging. The precise pathophysiological regulation of CL associated with mitochondria-mediated apoptosis, however, is still unclear. With the application of fluorescent probes and proteins coupled multi-photon laser scanning imaging microscopy, this study aims to mechanistically elucidate mitochondria-mediated CL pathophysiological regulation in live mitochondria of astrocytes. Specifically, the precise distribution of CL during both exogenous and endogeneous mitochondrial stresses induced by either pharmacochemical alterations or by mitochondrial respiratory chain (RC) defects in association with mROS, mCa2+, mitochondrial dynamics and the MPT will be explored in detail. In addition, precise vicious interaction and amplification among mitochondrial stresses in association with the alteration of CL distribution will be investigated. And comparison among various RC defect-induced mitochondrial stresses in association with the distribution of CL will be made in defected lines or cybrids and its parental wild type RBA1 astrocytes. Finally, we will explore the bioavailability of mitochondria-targeted protective maneuvers for the preservation of CL against various mitochondrial stresses by application of mitochondria-targeted antioxidants, Mito-Q and Mito-Vit E, mitochondria-targeted protector, melatonin, and photodynamic effect induced protective preconditioning. As astrocytes not only support the neuronal network but also actively involve in synaptic transmission and neurovascular coupling for neuron survival in the central nerve system, the information released from this study, thus, will provide potential clinical therapeutic manipulation and prevention of CL-mediated mitochondrial pathologies and neurodegenerative diseases

Project ID:PC10202-0647
External Project ID:NSC101-2320-B182-031-MY3