PerspectiveCell Biology

Modulating Mitochondrial Intracellular Location as a Redox Signal

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Science Signaling  18 Sep 2012:
Vol. 5, Issue 242, pp. pe39
DOI: 10.1126/scisignal.2003386

Abstract

Mitochondria have various essential functions in metabolism and in determining cell fate during apoptosis. In addition, mitochondria are also important nodes in a number of signaling pathways. For example, mitochondria can modulate signals transmitted by second messengers such as calcium. Because mitochondria are also major sources of reactive oxygen species (ROS), they can contribute to redox signaling—for example, by the production of ROS such as hydrogen peroxide that can reversibly modify cysteine residues and thus the activity of target proteins. Mitochondrial ROS production is thought to play a role in hypoxia signaling by stabilizing the oxygen-sensitive transcription factor hypoxia-inducible factor–1α. New evidence has extended the mechanism of mitochondrial redox signaling in cellular responses to hypoxia in interesting and unexpected ways. Hypoxia altered the microtubule-dependent transport of mitochondria so that the organelles accumulated in the perinuclear region, where they increased the intranuclear concentration of ROS. The increased ROS in turn enhanced the expression of hypoxia-sensitive genes such as VEGF (vascular endothelial growth factor) not by reversibly oxidizing a protein, but by oxidizing DNA sequences in the hypoxia response element of the VEGF promoter. This paper and other recent work suggest a new twist on mitochondrial signaling: that the redistribution of mitochondria within the cell can be a component of regulatory pathways.

We have known for a long time that mitochondria are at the heart of metabolism and are essential for adenosine 5′-triphosphate (ATP) supply, for core metabolism, and for the synthesis of essential cell components such as iron-sulfur centers, heme, and ubiquinone (13). More recently, our ideas of the roles of mitochondria have expanded considerably, and it is now clear that mitochondria are also central to other cell processes. For example, apoptotic cell death is regulated by interactions between proteins of the Bcl2 family on the mitochondrial outer membrane, which integrate pro- and antiapoptotic signals and determine commitment to apoptosis. When the balance of signals favor apoptosis, Bcl2 family members induce mitochondrial outer-membrane permeabilization (MOMP), releasing proapoptotic proteins from the mitochondrial intermembrane space to activate the caspase cascade (4). Mitochondrial oxidative damage, in conjunction with the uptake of calcium, leads to induction of the mitochondrial permeability transition pore, which is a major contributor to necrotic cell death (5, 6). There is growing evidence that mitochondria are involved in innate immunity by facilitating the assembly of the inflammasome (7). These and other examples make it clear that mitochondria are firmly integrated into cell function and fate: It is no longer a surprise to find mitochondria having a critical role in a process other than energy metabolism.

It is then to be expected that mitochondria contribute to many regulatory pathways that enable their function to adapt to local requirements and also to modulate cell activity. These regulatory pathways include simple feedback pathways by which mitochondrial oxidative phosphorylation is increased in response to increased ATP consumption by respiratory control, or by feedback inhibition to modulate electron supply to the respiratory chain (8, 9). Metabolic regulation can be extended to posttranslational modification of key steps of mitochondrial metabolism, such as altering the entry of carbohydrate into the Krebs cycle by the inhibitory phosphorylation of the pyruvate dehydrogenase complex by pyruvate dehydrogenase kinase (10, 11). The regulation of mitochondrial metabolic function can also be changed by external signals. For example, the increase in cytosolic calcium that occurs in many signaling events activates mitochondrial dehydrogenases and thus enables ATP production to match the demands of the increased work load (12). Changes in the amount of mitochondria in the cell and the abundance of mitochondrial proteins also enable the long-term adaptation of mitochondrial function to changing cell demands, for example, by sensing deficiencies in cellular ATP status through adenosine 5′-monophosphate (AMP)–dependent protein kinase (AMPK), which in turn can increase the expression of genes encoding mitochondria proteins by activating transcriptional coactivators such as peroxisome proliferator–activated receptor-γ coactivator–1α (PGC-1α) (1315).

In addition, mitochondria also participate in redox signaling (16, 17), a signaling mode in which the production of reactive oxygen species (ROS) or changes in redox couples such as glutathione or thioredoxin typically elicit changes in the activity of target proteins such as transcription factors (18, 19). Mitochondria are a major source of ROS in the cell and are involved in redox signaling pathways (17, 20). For example, a major ROS produced by mitochondria is hydrogen peroxide, which can diffuse from mitochondria and modify the activity of target proteins by oxidizing redox-sensitive thiols, which is reversed by the glutathione and thioredoxin pools once the signal has diminished (2123). Although the idea of feedback regulation of cytosolic processes in response to mitochondrial ROS production is appealing and is being explored in a number of contexts, it is a new area, and many of the details and the physiological importance of the processes are still unclear.

There is strong evidence that mitochondrial redox signaling participates in hypoxia sensing (24, 25). The response to hypoxia is regulated by the transcription factor hypoxia-inducible factor (HIF), which comprises HIF-1α and HIF-1β (24, 25). Under normoxic conditions, the high oxygen concentration leads to the hydroxylation of prolyl residues on HIF-1α, targeting it for degradation by the proteasome. Consequently, the HIF-1α and HIF-1β dimer is only activated during hypoxia and mediates the transcription of genes that enable the cell to adapt to and counteract hypoxia. During hypoxia, the production of mitochondrial ROS increases by a mechanism that is poorly understood and that seems to further stabilize HIF-1α (25), perhaps by inhibiting the prolyl hydroxylase enzyme, which mediates the modification of HIF-1α that targets it for degradation.

In parallel with our growing appreciation of the importance of mitochondrial redox signaling, there have also been advances in our understanding of mitochondrial dynamics. Mitochondria are not static organelles, and they continually fuse, separate, and move around the cell, driven by their connections to microtubules by dynein guanosine triphosphatases (GTPases) (26). The reasons underlying the continual fusing and separating are not well understood, but they are likely to include the autophagic turnover of damaged mitochondria and perhaps the response to different energy demands (27). The extent to which mitochondrial fission and fusion relate to their distribution within the cell is unclear but seems likely to be important, particularly in neuronal cells, in which mitochondria are trafficked along axons in both retrograde and anterograde directions by microtubules (26, 28).

Now, Al-Mehdi et al. (29) suggest a fascinating link between mitochondrial dynamics and redox signaling in hypoxia signaling. Hypoxia in pulmonary artery endothelial cells led to a net retrograde movement of mitochondria attached to microtubules that resulted in the perinuclear clustering of mitochondria (Fig. 1). This hypoxia-dependent relocalization increased the local concentration of ROS in the nucleus, presumably because of the diffusion of hydrogen peroxide from mitochondria. This local increase in ROS in the nucleus then increased the transcription of HIF-1α–dependent genes such as VEGF (vascular endothelial growth factor). Unexpectedly, the ROS signal did not operate by stabilizing HIF-1α but instead seemed to directly trigger sequence-specific DNA oxidation that modified the VEGF promoter and facilitated transcriptional complex assembly on these promoters. Of course, many questions remain. The mechanism by which hypoxia alters mitochondrial localization is not clear. The nature of the DNA modification is also uncertain, and whether this can be subsequently reversed was not determined. There is much to be learned about the mechanisms of how mitochondrial movement is controlled, and many new directions for research are suggested. One of the most intriguing ideas is that the relocalization of mitochondria can be part of a signaling pathway, and this relates to other work in which the localization of mitochondria around a phagosome increases mitochondrial ROS and thereby increases bacterial killing (30). Al-Mehdi et al. showed that ROS was the signal modified through the altered mitochondrial localization, but the same principle can apply to modulating other signaling molecules. For example, there is growing interest in the effect of mitochondrial localization on calcium signals, and mitochondria can localize to the plasma membrane to modulate calcium signals (31). Another surprise was the modification of transcription by the oxidative modification of DNA within a promoter by ROS, and it will be important to see whether this is a general method of transcriptional regulation.

Fig. 1

A model for hypoxia signaling by mitochondrial relocalization. (Top panel) Mitochondria are distributed throughout the cells and connected to microtubules. (Lower panel) Upon exposure to hypoxia, the mitochondria undergo retrograde movement on microtubules and become concentrated around the nucleus. This in turn leads to the increased diffusion of ROS such as hydrogen peroxide from the mitochondria into the nucleus. (Inset) The increased ROS leads to an increased expression of hypoxia-sensitive genes such as VEGF through the oxidative modification of DNA in the upstream hypoxia response element.

CREDIT: Y. HAMMOND/SCIENCE SIGNALING

This stimulating paper suggests new ways in which mitochondrial location may change cell function. It may be that this redistribution occurs in response to many other signals other than hypoxia, and it is likely that the interplay between mitochondrial localization as well as fission and fusion will be an important aspect of this. It will be interesting to see whether this mechanism is general and to explore the extent to which disruption to mitochondrial localization within the cell contributes to a pathological situation such as in cancer, ischemia-reperfusion injury, and inflammation. It may then be possible to treat the distribution of mitochondria within the cell as a therapeutic target.

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