Mitochondrial signaling pathways: A receiver/integrator organelle

Research over the last decade has extended the prevailing view of cell mitochondrial function well beyond its critical bioenergetic role in supplying ATP. Recently, it has been recognized that the mitochondria play a critical role in cell regulatory and signaling events, in the responses of cells to a multiplicity of physiological and genetic stresses, inter-organelle communication, cell proliferation and cell death. Nevertheless, a broad-based review on mitochondrial signaling is not presently available. To bridge that gap, this review examines the perspective of mitochondria as the receiver integrator and transmitter of signals, dissecting the multiple and interrelated signaling pathways at both the molecular and biochemical levels with particular focus on nuclear and cytoplasmic factors, fundamentally involved in the shaping of the organelles' responses. We examine evidence that the mitochondria act as a dynamic receiver and integrator of numerous translocated signaling proteins (including protein kinases and transcription factors), regulatory Ca2+ fluxes and membrane phospholipids as well the transmission of mitochondrial-generated oxidative stress and energy-related signaling. Novel experimental approaches studying mitochondrial signaling including cell studies using metabolic inhibitors and genetic stresses (e.g. mtDNA depletion) are discussed. While there is abundant interest and information concerning its integral role to apoptosis, mitochondrial signaling also plays a fundamental role in proliferative pathways, nutrient sensing, inter-organellar cross-talk and in the responses of cells to metabolic transition and physiological stresses which remain relatively unexplored. (Mol Cell Biochem 262: 1–16, 2004)