
Kyle McCommis, Ph.D.
Assistant Professor
Studies on the fundamental aspects of mitochondrial metabolism and novel areas of inter-organ and cell-to-cell communication.
Research Interests
My lab is focused on mitochondrial metabolism and its role in human disease. We have two major research directions.
One project explores the role of mitochondrial metabolism in heart failure. We will study the connection between heart failure and altered hepatic metabolism and signaling due to ketone body production in the liver. Our studies will use isolated and perfused mouse hearts, where we can perform live metabolic measurements, as well as isolation of primary hepatocytes.
A second project will study the role of mitochondrial metabolism in the activation of hepatic stellate cells and their role in liver fibrosis. This new line of research aims to study reducing hepatic fibrosis through inhibition of mitochondrial metabolism and could be significant for treatment of human disease.
Recent Publications
Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier
Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier
Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties. To address this, approximately 50 pyrazole-based MPC inhibitors were synthesized to explore the structure-activity relationship for MPC inhibition, evaluated through inhibition of mitochondrial pyruvate respiration. These inhibitors were designed with increased steric hindrance around electron-deficient double bonds, allowing for refined structural modifications that reduce their potential to act as Michael acceptors. Additionally, the new MPC inhibitors directly inhibited stellate cell activation, indicating their potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Unlike the thiazolidinedione class of MPC inhibitors, these compounds did not activate the nuclear receptor PPARγ. Molecular modeling was conducted to explore interactions between these novel inhibitors and the MPC complex. We have identified the chemical determinants critical for MPC inhibition and successfully developed novel inhibitors that are potent, specific and possess excellent physicochemical properties, high solubility, and outstanding metabolic stability in human liver microsomes.
Metabolic dysfunction and insulin sensitizers in acute and chronic disease
Metabolic dysfunction and insulin sensitizers in acute and chronic disease
The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of ‘insulin resistance’ as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases.
Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer
Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer
Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways
Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways
One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.
Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons
Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons
Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we find that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs. Disruption of OMDs potentiated action potential firing in nociceptor DRG neurons and facilitated the opening of native hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels. This increased neuronal firing is partially due to an increased open probability and altered gating kinetics of HCN channels. The gating effect on HCN channels is likely due to a direct modulation of their voltage sensors by OMDs. In animal models of neuropathic pain, we observe reduced OMD size and a loss of HCN channel localization within OMDs. Additionally, cholesterol supplementation inhibited HCN channels and reduced neuronal hyperexcitability in pain models. These findings suggest that disturbances in lipid nanodomains play a critical role in regulating HCN channels within nociceptor DRG neurons, influencing pain modulation.