AbstractDietary methionine restriction (MR) is associated with a spectrum of health‐promoting benefits. Being conducive to prevention of chronic diseases and extension of life span, MR can activate integrated responses at metabolic, transcriptional, and physiological levels. However, how the mitochondria of MR influence metabolic phenotypes remains elusive. Here, we provide a summary of cellular functions of methionine metabolism and an overview of the current understanding of effector mechanisms of MR, with a focus on the aspect of mitochondria‐mediated responses. We propose that mitochondria can sense and respond to MR through a modulatory role of lipoylation, a mitochondrial protein modification sensitized by MR.