We aim to identify the new molecular regulators and events involved in mitochondrial calcium flux/sensing, mitochondrial structural homeostasis, protein quality control, cell death, and how they contribute to the onset of cardiovascular diseases. To gain in-depth knowledge of mitochondrial organization and functions, we utilize multidisciplinary approaches including cell and molecular biology techniques, protein biochemistry, calcium flux analysis, cellular respiration measurements, omics-based approaches, live-cell imaging, mutant and transgenic mouse models, and in vivo physiological methods. 

Current Projects

Calcium signaling and mitochondrial ionic homeostasis

Research results.Calcium is the second most abundant metal ion in the biological system and regulates numerous cellular functions by binding distinct calcium-sensing domains or motifs present on numerous proteins. The calcium concentration varies greatly between different cellular compartments, and thus calcium sensors are strategically localized for subcellular/organelle-specific signaling. Mitochondria actively regulate their calcium concentration and contain calcium sensors to mediate anterograde and retrograde signaling. Mitochondrial calcium participates in cellular energy production through the regulation of bioenergetics yet can also promote different modes of cell death. Calcium is also involved in the regulation of mitochondrial trafficking, structural homeostasis, and dynamics. Dysregulation of mitochondrial calcium flux has been linked to numerous cellular dysfunctions, including chronic oxidative burden, autophagy, and sensitization for cell death, which are the central hallmarks of the multiple pathologies. We aim to identify the new regulators and regulatory events associated with mitochondrial calcium-sensing/flux and their role in animal physiology using protein biochemistry, high-end imaging-based approaches, and genetic manipulations. 

Mitochondrial Ultrastructural Remodeling and Inter- Organelle Crosstalk 

Research results.Mitochondrial membranes form an intricate network of contact sites within or with the adjacent mitochondria or other cellular organelles. Outer mitochondrial membrane (OMM) forms transient contact sites with other organelles that determine mitochondrial and overall cellular health. The inter-and intramembrane junctions of the OMM and inner mitochondrial membrane (IMM) are the prime sites for the multiple signaling and bioenergetic events that shape up the mitochondria's physiological outcome. The IMM invaginates to form the cristae structure and harbor three to the tenfold large surface area than OMM. The large IMM surface area allows the mitochondrion to pack a large number of protein complexes in a small volume to make highly efficient energy generators. The inter- mitochondrial OMM contacts are essential for mitochondrial fusion as well as communication between two mitochondria. Emerging evidence suggests that mitochondrial membranes and contact sites are disorganized in multiple pathological conditions and serve as a universal hallmark of mitochondrial dysfunction. We aim to identify the molecular determinants and signaling events associated with mitochondrial contact sites and mitochondrial membranes architecture.

Protein Quality Control 

Research results.The mitochondrial proteome includes around two thousand proteins. Around 99% of the mitochondrial proteins are nuclear-encoded that are synthesized on the endoplasmic reticulum, or cytosol, or the mitochondrial surface. These mitochondrial proteins are subsequently imported into the mitochondria. Multiple post-translational modifications and protein quality control processes are involved in mitochondrial protein import, folding, assembly into multimeric protein complexes, protein functions, and regulated turnover. Defects in mitochondrial protein quality control machinery result in mitochondrial dysfunction that leads to the failure of cellular homeostasis and the onset of diseases. Our research aims to identify the molecular determinants of the mitochondrial protein quality control mechanisms and delineate the associated molecular events that lead to disease onset. 

Cardiac Physiology & Metabolism

Research results.Heart diseases are the number one cause of death in the US and represent substantial health and economic burden. Mitochondrial dysfunctions and mitochondria-initiated cell death signaling are the primary cause of cell loss associated with the progression of heart failure. Our research focuses on the identification of new molecular regulators and events associated with the mitochondrial (dys)functions and mitochondria-initiated cell death signaling. We aim to characterize the molecular consequences of these signaling events using mouse genetics and physiology-based in vivo methods.