Serial Review: The powerhouse takes control of the cell: The role of mitochondria in signal transduction Serial Review Editor: Victor Darley-Usmar
Kinase signaling cascades in the mitochondrion: a matter of life or death

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Abstract

In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase-mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation and immunofluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.

Introduction

Dynamic networks of signaling cascades mediate the communication of localized events to other regions of the cell, allowing appropriate cellular and tissue responses to opportunities or stresses in the larger environment. The translocation of activated signaling proteins from the cell membrane to the nucleus, where the rate of transcription of specific genes is altered, is easily the most familiar form of signal transduction. However, it is by no means the only route that signaling molecules can take. Localization of activated protein kinases to specific cytoplasmic subcompartments mediates important processes such as cell motility [1], and signaling endosomes may facilitate long distance communication in neurons [2]. In addition to classic hormone- or growth factor-initiated signaling cascades, recent advances in redox regulation of signaling pathways adds to the complexity of signals that must be integrated to produce a functional outcome. The mitochondrion is ideally suited as a point of integration for these signaling cascades due to its pivotal role in cellular metabolism, redox biochemistry, and survival–death decisions.

Following development of the endosymbiotic theory of mitochondrial origin, characterization of enzymes in carbohydrate, lipid, amino acid, and nucleotide metabolism, and the elucidation of the Krebs cycle and electron transport chain, the mitochondrion has reemerged as a central mediator of cell death signaling [3]. Aside from extensive work with Bcl-2 family members and release of mitochondrial death mediators [4], [5], [6], [7], relatively little is known about how this organelle communicates with the rest of the cell. Even in healthy nondying cells, regulation of mitochondrial numbers in relation to cellular needs would require coordinated transcription of nuclear and mitochondrial genes and the genesis or trafficking of mitochondria to appropriate regions of high-energy utilization [8]. Likewise, mechanisms for signaling autophagic degradation of aged or damaged mitochondria also remain to be elucidated [9], [10], [11].

In recent years, numerous studies have consistently demonstrated that certain components of well-known kinase signaling cascades are specifically targeted to mitochondria, where they modulate mitochondrial activity and the release of mitochondrial products that ultimately affect the entire cell. While the majority of these studies have focused on the mitochondrion as a recipient and integrator of cell survival/death signals, components of the respiratory chain are also regulated by phosphorylation [12], [13], [14]. Additionally, several of these kinase pathways are subject to regulation by reactive oxygen and nitrogen species. Specific mechanisms by which redox tone can regulate cell signaling pathways have been previously reviewed [15], [16], [17], [18], [19]. The following discussion focuses on kinase regulation of mitochondrial function and studies that demonstrate localization of activated kinases within mitochondrial subcompartments. As reactive oxygen/nitrogen species are typically short-lived, definitive mitochondrial localization of kinases suggests additional mechanisms for reverse signaling from mitochondria to the rest of the cell.

Section snippets

Protein kinase A

The protein kinase A (PKA) signaling pathway mediates a multitude of responses to hormonal stimulation which are often cell type specific (for review, see [20]). The classic PKA pathway involves the binding of an extracellular molecule to a G protein-coupled receptor, which catalyzes the formation of intracellular cyclic AMP through the activation of adenylate cyclase. Cyclic AMP then binds to the two regulatory subunits of PKA, thereby releasing the two catalytic subunits to phosphorylate

PI3K/Akt/PKB

The serine/threonine kinase Akt (protein kinase B) plays a major role in cell proliferation and survival in many cell types. Akt is classically activated by phosphoinositide-dependent kinases following recruitment to the plasma membrane by products of the type I phosphoinositide 3-kinase [35]. Antiapoptotic effects of nitric oxide may be partially mediated through cGMP-dependent activation of phosphoinositide 3-kinase and Akt [36]. In addition to direct effects of Akt in phospho-inactivating

Protein kinase C

The protein kinase C (PKC) family consists of multiple isozymes with distinct distribution patterns in different tissues [45]. Binding of an extracellular ligand to a receptor tyrosine kinase or G protein-coupled receptor activates phospholipase C, which produces inositol triphosphate (IP3) and diacylglycerol (DAG). Calcium liberated by IP3 causes PKC to bind to membranes, where DAG then activates it. Activated PKC phosphorylates many targets, including c-Fos and NF-κB. It is important to note,

Raf-MEK-ERK

The extracellular signal regulated protein kinases (ERK1/2) are integrally involved in regulating pivotal processes including proliferation, differentiation, adaptation (i.e., cell motility, long term potentiation), survival, and even cell death. The three-tiered ERK signaling module involves sequential activation of Raf (MAPKKK), MEK1/2 (MAPKK), and ERK1/2 (MAPK). Depending on its intracellular localization and pathway of activation, Raf-1 can affect apoptosis by different mechanisms [38], [63]

JNK/SAPK and p38 MAPK

The two other major branches of the MAPK family, the p38 MAPKs and the c-Jun N-terminal kinase (JNK or stress-activated protein kinase (SAPK) have both been extensively implicated in prodeath signaling (reviewed in [97]). Like ERK, p38 and JNK are activated by a MAP kinase kinase (MKK), which in turn is activated by a MAPKKK in response to a stimulus. The stimulus may include oxidative stress, irradiation, or proinflammatory cytokines such as tumor necrosis factor α.

Many studies indicate a role

Conclusions

Mitochondrial alterations have been implicated in a wide variety of acute and chronic human conditions, including cancer, intoxication, neurodegenerative diseases, and aging [118], [119], [120], [121]. For example, not only are there complex I deficiencies in sporadic Parkinson's disease [118], but also mutations in mitochondrially targeted proteins, including a putative kinase [122], have been recently identified in autosomal recessive forms of the disease [123], [124]. Kinase signaling

Acknowledgment

Research in the author's laboratory is supported by the National Institutes of Health (R01 NS40817).

Craig Horbinski received his M.D. and Ph.D. degrees in 2003 from the State University of New York at Buffalo. He is currently a resident in the Department of Pathology at the University of Pittsburgh.

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    Craig Horbinski received his M.D. and Ph.D. degrees in 2003 from the State University of New York at Buffalo. He is currently a resident in the Department of Pathology at the University of Pittsburgh.

    Charleen T. Chu received her Ph.D. in 1993 and her M.D. in 1994 from Duke University, followed by research and clinical fellowships in cell signaling and neuropathology. She is currently Associate Professor of Pathology and Ophthalmology at the University of Pittsburgh, with research interests in oxidative stress, cell signaling, and alternative neuronal death styles. Work from her laboratory implicates altered patterns of phospho-ERK localization and autophagic cell death in parkinsonian pathogenesis.

    This article is part of a series of reviews on “The Powerhouse Takes Control of the Cell". The full list of papers may be found on the home page of the journal.

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