Mitochondrial signaling pathways: A receiver/integrator organelle

Abstract

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.

Mitochondrial protein phosphorylation: instigator or target of lipotoxicity?

“…It has been shown that mitochondrial kinases and phosphatases are under the control of intraluminal Ca 2+ [18], an effector that is already known to adjust the activity of many metabolic and anti-oxidative enzymes within mitochondria [12,17]. This observation indicates that mitochondrial Ca 2+ accumulation is a crucial phenomenon for the immediate regulation of mitochondrial protein phosphorylation.…”

“…Mitochondria then integrate these inputs, adapting their activity and functions to, ultimately, tune cellular responsiveness with respect to the current demand of the cell [12] (Figure 1). In spite of the important tasks of the mitochondrion and in contrast to its functions in energy metabolism, its contribution to signal transduction has not been thoroughly investigated, and the [24,25].…”

“…free fatty acids, triglycerides and phospholipids) or D-glucose not only represents a tremendous metabolic challenge but also affects the functionality of this organelle [13]. Thus, in most metabolic disorders, mitochondrial dysfunction occurs regardless of substrate type and contributes to cell and tissue dysfunction [12]. However, most reports focus on excessive mitochondrial reactive oxygen species (ROS) production and mitochondrial-dependent apoptosis as the common endpoint of such a calamitous development [14], and little is known about the molecular events that are responsible for initial changes in the mitochondrial relay function to substrate overload and the consequences for the cell signal-transduction machinery.…”

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

“…Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1,2). Despite their importance, signaling into, from, and within mitochondria is still not well understood.…”

Characterization of Jumping translocation breakpoint (JTB) gene product isolated as a TGF-β1-inducible clone involved in regulation of mitochondrial function, cell growth and cell death

“…Mitochondria are primarily energy-generating systems, the final step of which is oxidative phosphorylation coupled with an electron transport chain, supplying ATP. Having a pivotal role in the bioenergetic process, mitochondria are also critical to signaling events, receiving and integrating dynamically a wide range of signaling molecules from calcium ion to protein kinases, receptors and transcription factors (Goldenthal and Marin-Garcia, 2004). Although numerous studies have focused on the integral role of mitochondrial signaling cascades in apoptotic progression, mitochondrial signaling is prominently involved in proliferative pathways, nutrient sensing, inter-organellar communication and stress responses of cells (Goldenthal and Marin-Garcia, 2004).…”