Research

The Finck Lab is interested in two general areas of intermediary metabolism.

A primary focus over the past few years has been on mitochondrial metabolism of pyruvate as regulated by the mitochondrial pyruvate carrier complex. This work has also led us to focus on other facets of mitochondrial metabolism as well.

More recently, we have also been interested in the molecular regulation of amino acid metabolism in the liver and other organs.

The role of the mitochondrial pyruvate carrier (MPC) in health and disease

Pyruvate is a three-carbon intermediate that is synthesized in the cytosol as the end product of glycolysis, by the oxidation of lactate, and from a variety of amino acids. However, in order to undergo further metabolism by oxidation or carboxylation, pyruvate must cross the impermeable inner mitochondrial membrane to enter the mitochondrial matrix. The transport of pyruvate into the mitochondrion is mediated by the mitochondrial pyruvate carrier (MPC); a heterodimeric complex of two proteins MPC1 and MPC2.

Once in the mitochondrial matrix, pyruvate can be oxidized by pyruvate dehydrogenase (PDH) to generate acetyl-CoA, which many types of cells use to produce reducing equivalents (NADH) to drive ATP synthesis. Pyruvate can also be carboxylated by pyruvate carboxylase (PC) to form oxaloacetate (OAA) in an anaplerotic reaction. OAA can be condensed with acetyl-CoA to form citrate or converted to malate. These reactions are required and critical for a variety of biological and biosynthetic pathways including synthesis of glucose via gluconeogenesis, de novo lipogenesis, and synthesis of neurotransmitters and other lipids.

Work to date has demonstrated important roles for the MPC in regulating metabolism in liver, heart, and pancreatic beta cells. We are very interesting in the development and implementation of MPC inhibitors for treating diabetes, nonalcoholic fatty liver disease, and other metabolic diseases.

Regulation of amino acid homeostasis

Amino acids are used by the body to synthesize new proteins and biomolecules and, in some metabolic states, are an important substrate used by the cell as a source of energy.

Our prior work on the mitochondrial pyruvate carrier revealed that alterations in amino acid metabolism constitute one of the most striking and most consistent effects of inhibiting the MPC across many cell types. This important observation led us to become interested in amino acid metabolism, with a primary focus on alanine, glutamine, and branched chain amino acids (BCAA; leucine, isoleucine, and valine). These amino acids are important mitochondrial substrates for both catabolic and anabolic reactions, but many mechanisms regulating their metabolism remain poorly understood. We have shown that when the MPC is inhibited, cells compensate by increasing the use of these amino acids. Moreover, we believe that these compensatory changes are important for the beneficial effects we observe with MPC inhibition in many cases. Other ongoing studies are focused on understanding fundamental mechanisms regulating the oxidation of the essential branched chain amino acids, which is impaired in a variety of cardiometabolic disease states.

This work will have important implications for gaining a better understanding of these processes and may lead the way to new targeted approaches to modulate amino acid metabolism with implications for treating diabetes, MASLD, and cancer.

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