Mitochondrial impairment is a main contributor and potential therapeutic target in the development of heart failure (HF). During excitation-contraction coupling, Ca2+ is released from the sarcoplasmic reticulum of dyadic junction (jSR) to initiate muscle contraction. jSR is often tethered to mitochondria, where a high [Ca2+] nanodomain is created to facilitate Ca2+ propagation to the mitochondrial matrix to stimulate ATP production (excitation-energetics coupling). The beating heart consumes much energy; thus, cardiomyocytes must be efficient in dynamically balancing energy demands and supplies while avoiding potential Ca2+ mediated toxicity. We find that mitochondrial Ca2+ uniporter (mtCU), responsible for Ca2+ uptake, concentrate to hotspots at the interface with jSR whereas the robust Na+-dependent Ca2+ extrusion (mitochondrial Na+/Ca2+ exchanger, NCLX) is mostly excluded from these segments. In this proposal, we put forward the overarching theme that the mitochondria, which associate with jSR, remodel their membrane structure and protein distribution asymmetrically into two zones proximal and distal from jSR, to protect their long-term integrity while serving the excitation-energetics coupling. Imbalance in this adaptation leads to HF. Based on our preliminary data and published literature; we hypothesize that mitochondrial Ca2+ influx and efflux are uniquely distanced, and so a [Ca2+] gradient is created in the matrix to ensure an effective Ca2+ mediated energy production without toxicity by minimizing the amount of Ca2+ required to cycle through the matrix for a given [Ca2+] rise. The mitochondrial zone proximal to the jSR forms a Ca2+ receptacle with enhanced Ca2+ entry but limited exit and less membrane barriers for diffusion, while the mitochondrial zone distal to jSR has dense cristae membrane for vigorous ATP generation without subjecting to Ca2+ toxicity. Finally, the constant high Ca2+ in Ca2+ receptacle zone renders it more susceptible for physiological mitophagy via mitochondrial fission. However, prolonged stress turns this physiological defense mechanism maladaptive, with excess of fragmented mitochondria without jSR Ca2+ input (no excitation-energetics coupling) due to the loss of juxtaposition, as such leads to HF etiology.
Three specific aims are: 1) Investigate the physiological implications of differential submitochondrial distribution of mitochondrial Ca2+ uptake and extrusion mechanisms in excitation-energetics coupling. 2. To establish submitochondrial structural zoning associated with the zonal Ca2+ transport. 3. To assess the impact of zoning on mitochondrial maintenance/quality control and how excessive fragmentations associated with stresses could turn zoning maladaptive and lead to HF.
This study aims to elucidate the mechanisms of how mitochondria adapt to their local environment via strategic, zonal distribution of key transport proteins and re-organization of cristae. Moreover, how maladaptive zonal distribution can cause mitochondria-mediated contractile dysfunction and so heart failure. The new knowledge to be obtained will add to our understanding in how this signaling mechanism can regulate the energy metabolism of the heart. This new knowledge will help us to find means to keep our heart healthy daily and cure the disease when it becomes unhealthy.
