Mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase (Complex I/mGPDH)

Mitochondrial complex I (NADH:ubiquinone oxidoreductase) and mitochondrial glycerophosphate dehydrogenase (mGPDH) are critical enzymes involved in cellular energy metabolism and redox balance (UniProt P03886, P43304). Complex I is the first and largest component of the mitochondrial electron transport chain, responsible for oxidizing NADH and contributing to the proton gradient for ATP production (PubMed: 10839993). mGPDH is a key component of the glycerol-3-phosphate shuttle, which transfers reducing equivalents from the cytosol to the mitochondria, thereby maintaining the cytosolic NAD+/NADH ratio (Nature: 24847880). Together, these targets play a pivotal role in regulating hepatic gluconeogenesis and systemic glucose levels. Drugs like metformin inhibit these enzymes to alter the NADH/NAD+ ratio and increase cellular AMP levels, which suppresses glucose production in the liver (Nature: 24847880). This dual inhibition is a primary mechanism for treating type 2 diabetes and is being explored for potential anti-cancer applications due to its impact on cellular bioenergetics (PubMed: 27508874). While Complex I inhibition is a well-established effect of biguanides, the specific role of mGPDH inhibition has emerged as a significant contributor to the suppression of gluconeogenesis from lactate and glycerol (Nature: 24847880). Therapeutic modulation of these targets requires careful management to avoid excessive inhibition, which can lead to metabolic complications such as lactic acidosis (PubMed: 20371550).

Other names

NADH:ubiquinone oxidoreductaseGlycerol-3-phosphate dehydrogenase 2 (mitochondrial)GPD2Complex ImGPDHNADH dehydrogenase

Inhibition of mitochondrial respiratory chain Complex I and mitochondrial glycerophosphate dehydrogenase leads to a decrease in hepatic gluconeogenesis by altering the cytosolic and mitochondrial redox states and increasing the AMP:ATP ratio, which subsequently activates AMP-activated protein kinase (AMPK) (Nature: 24847880; PubMed: 10839993).