Department of Physiology Zoom seminar, Tuesday, June 30, at 3:30PM

Dr. Patgiri will present a Zoom seminar entitled “An engineered enzyme therapeutic for mitochondrial disease” on Tuesday, June 30, 2020, from 3:30-4:30pm. Zoom call-in particulars are included below. PLEASE NOTE: This is a password-protected login.

Dr. Patgiri received his Ph.D. in Organic Chemistry from New York University. He then continued into postdoctoral work at Rockefeller University before moving to Massachusetts General Hospital and Harvard Medical School, where he is currently a postdoctoral fellow in the lab of Dr. Vamsi K. Mootha. 

Abstract: The mitochondrial electron transport chain (ETC) produces the majority of cellular ATP while oxidizing redox cofactor NADH to NAD+ in a process called oxidative phosphorylation (OXPHOS). Although the lack of OXPHOS-derived ATP has classically been considered as the main driver of mitochondrial disease, recent studies suggest that an elevated intracellular NADH/NAD+ ratio (known as “reductive stress”) caused by a defective ETC contributes significantly to the disease pathology. Reductive stress inhibits multiple essential NAD+-coupled pathways including glycolysis which is the primary source of ATP in cells with dysfunctional mitochondria. Therefore, we hypothesized that alleviation of reductive stress could be therapeutic for diseases caused by ETC dysfunction.

To test this hypothesis, we have engineered an enzyme (named “LOXCAT”) with the aim to lower the blood lactate/pyruvate ratio to them secondarily normalize disease-associated elevations in the tissue NADH/NAD+ ratio. This strategy takes advantage of the well-established equilibrium between the blood lactate/pyruvate and the tissue NADH/NAD+ ratios. LOXCAT is an engineered fusion of the enzymes lactate oxidase (LOX) and catalase (CAT) and produces pyruvate and water from lactate and oxygen. Proof of concept cell culture experiments showed that LOXCAT added to the media of cells with ETC dysfunction significantly lowered the extracellular lactate/pyruvate ratio and normalized the intracellular NADH/NAD+ ratio. Such mitigation in reductive stress allowed cells to restore glycolytic ATP production and rescue proliferation.

In a chemically-induced mitochondrial disease mouse model, tail vein-injected LOXCAT normalized disease-associated elevations in the brain and heart NADH/NAD+ ratios by lowering the blood lactate/pyruvate ration (Patgiri et al., Nat Biotech 2020). These data showed for the first time that the circulating lactate/pyruvate ratio functions as a systemic regulator of the tissue NADH/NAD+ ratio. We are currently testing if LOXCAT could attenuate ETC disease symptoms in mouse models. Together, LOXCAT lays the foundation for a novel class of therapeutics that targets circulating metabolites to impact tissue redox homeostasis in mitochondrial disease.

We look forward to seeing everyone Tuesday afternoon!