Study the Role of Ca2+-Mediated Cardiolipin Remodeling and Mitochondrial Dynamics in the Pathological “Threshold Effect” of Mitochondrial Diseases

Studies of human mitochondrial diseases reveal a unique “threshold effect” that the final mitochondrial pathological outcomes in patients often occur only when certain degrees of mitochondrial DNA (mtDNA) mutation (representing mitochondrial respiration chain (RC) defects) are reached. The precise molecular mechanisms behind “threshold effects”, however, remain unclear. Our previous studies demonstrated that defected RC caused by either mitochondrial complex toxins or by mtDNA mutation, in addition to generate mitochondrial reactive oxygen species (mROS), induces significant mCa2+-mediated depletion of cardiolipin (CL) to alters mitochondrial membrane potential (△Ψm) for reduced ATP formation as well as to trigger the mitochondrial permeability transition (MPT) for lethal proteins release and final apoptosis of cells. RC defects also result in retardation of mitochondrial movement, enhanced fission and reduced fusion. Recently, autophage of mitochondria (mitophage) has been reported to involve in mitochondrial diseases. With the application of fluorescent probes and proteins coupled multi-photon laser scanning imaging microscopy, this study thus aims to mechanistically elucidate the specific role of mCa2+-mediated CL remodeling in the pathological “threshold effect” of mitochondrial diseases and to explore its potential targeting for a protective rearrangement of the pathological “threshold effect” for treatment. An alley of human Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) cybrids including parental 143B osteosarcoma cells (normal parental cells as control), ρ0 143B (mtDNA less 143B cells) and, 60% (no pathological symptom) vs. 98% (meets the threshold for pathological symptoms) mtDNA T8993G cybrids will be used. We proposed NARP-augmented “threshold effect” during mCa2+ stress is mediated by multiple gating of complex V defect-associated resetting the sensitivity of mCa2+ uniporter, the kinetics of mCa2+ fluctuation and hence the mCa2+-mediated CL remodeling and its down streams modulation of mROS formation and the MPT. And lastly, NARP-augmented alteration on mitochondrial movement, fission and fusion and mitophage may also crucially involve in regulating the final percentage of mutant mtDNA for the final pathological outcome of mitochondrial diseases. As mitochondrial diseases are often fatal and lack of effective therapeutic treatment, unveiling the precise regulatory role behind RC defect-associated mCa2+-mediated CL remodeling in “threshold effect” as well as protective alterations on these mechanisms proposed in this study thus can be crucial for potential therapeutic prevention of the pathological symptoms of mtDNA T8993G NARP.

Project ID:PC10507-0249
External Project ID:MOST105-2320-B182-011