Heme is an essential iron-containing cofactor that supports diverse biological processes, including oxygen transport, mitochondrial respiration, and xenobiotic metabolism. Beyond these canonical functions, accumulating evidence has established heme as a dynamic signaling molecule that couples mitochondrial metabolic state to cellular stress responses, gene expression, and metabolic adaptation. Heme biosynthesis is compartmentalized between mitochondria and the cytosol, requiring tightly coordinated synthesis, trafficking, sensing, and degradation to maintain cellular homeostasis and prevent heme toxicity. In this review, we examine mechanisms by which heme regulates mitochondrial protein quality control, respiratory chain assembly, and metabolic feedback to coordinate organellar function with cellular energy demands. We further discuss how heme is trafficked to extramitochondrial compartments, where it modulates cytoplasmic stress signaling, iron homeostasis, transcriptional networks, and metabolic programs through interactions with proteins, including the BACH1 transcription factor, REV-ERB nuclear receptors, and the glycolytic enzyme GAPDH. We also highlight ongoing debates surrounding mitochondrial heme trafficking and identify critical unanswered questions regarding the identity of intracellular heme chaperones and mitochondrial heme sensors. Finally, we discuss how dysregulation of heme synthesis, trafficking, sensing, and degradation contributes to diverse pathologies. Collectively, recent advances establish heme as a central regulator of mitochondrial communication and cellular homeostasis, underscoring the therapeutic potential of targeting heme signaling pathways in human disease.
