Metformin primarily inhibits mitochondrial respiratory chain complex I, leading to reduced oxidative phosphorylation. This results in decreased cellular ATP production and promotes anaerobic metabolism, causing accumulation of lactic acid. The impaired mitochondrial function diminishes the conversion of lactate to glucose via gluconeogenesis, further increasing lactate levels. This mechanism underlies metformin-associated lactic acidosis, especially in conditions predisposing to hypoxia or impaired drug clearance.

Reference: Harrison's Principles of Internal Medicine, J. Larry Jameson, 20th Edition.