PerspectiveCell Biology

O ROM(e)O1, ROM(e)O1, Wherefore Art Thou ROM(e)O1?

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Science Signaling  28 Jan 2014:
Vol. 7, Issue 310, pp. pe2
DOI: 10.1126/scisignal.2005024


Mitochondria are not only a source but also a target of reactive oxygen species (ROS). However, the molecular mechanisms by which ROS affect mitochondrial function are poorly defined. In this issue, Screaton and colleagues report that ROS modulator protein 1 (ROMO1) links ROS and mitochondrial morphology and ultrastructure by modulating cristae remodeling and mitochondrial fusion that depends on the guanosine triphosphatase Opa1. Their work indicates how the oxidative milieu triggers mitochondrial shape changes.

Reactive oxygen species (ROS) are necessary by-products of life in an oxygen-containing environment. Due to the imperfection of the molecular machines coupling electron flow to oxygen reduction to synthesize ATP, reaction intermediates in the form of singlet oxygen are released. Not only are they toxic by-products for which sophisticated detoxification systems are in place, but cellular processes have also evolved to use them as signaling molecules or tools to kill invading pathogens (1). Because they are the site of cellular respiration, mitochondria are abundant ROS producers. The major ROS sources are the electron transport chain (ETC) in the inner membrane, monoamine oxidase in the outer membrane, and p66Shc life-span protein in the intermembrane space (2). ROS production is counterbalanced by specific antioxidant systems such as superoxide dismutase, glutathione reductase, catalase, and thioredoxins. When antioxidants are overwhelmed by the produced ROS, proteins, DNA, and lipids undergo oxidative modifications. As might be expected, mitochondrial structures are particularly exposed to oxidative modifications that, in several pathologies (including cancer, diabetes, and neurodegenerative and cardiovascular diseases), help to establish a vicious circle between oxidative stress and mitochondrial dysfunction (3).

Changes in mitochondrial morphology are believed to cause or at least to accompany oxidative stress (4). In most cell types, mitochondria form an interconnected and dynamic network regulated by the continuous balance between fusion and fission events. In neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases, oxidative stress accompanies mitochondrial fragmentation (5). In hyperglycemic neurons, increased fission appears to be a requisite for ROS overproduction (6), and inhibition of mitochondrial fission can even block ROS production and cellular dysfunction triggered by ETC inhibitors (7). These reported changes impinge on the molecular mediators of fusion and fission: the profusion proteins mitofusin (MFN) 1 and 2 and Optic atrophy 1 (OPA1) and the profission proteins dynamin-related protein 1 (DRP1), Fission 1, mitochondrial fission factor, and mitochondrial division 49 and 51 (8). Drp1 has been proposed to be nitroxylated in Alzheimer’s disease, but the relevance of this modification for inducing mitochondrial fission is unclear (9). Mfns are activated by reduced glutathione to fuse mitochondria (10), yet so far the precise link between oxidative stress and mitochondrial morphology remains unclear. The possibilities are many: Mitochondria-shaping proteins could be directly modified by Cys oxidation and nitroxylated; or their activity could be modulated directly, in the case of Mfns, by the redox milieu of the cell; or their function could be modulated by redox sensors that translate redox changes into fusion or fission of mitochondria. Although this latter possibility is very appealing, so far no redox modulator of mitochondrial morphology had been discovered. In this issue, Screaton and colleagues describe their use of a high-content screening for modulators of mitochondrial morphology to identify the pleotropic protein ROMO1 (ROS modulator protein 1) as a redox adaptor of mitochondrial shape (11). Perhaps they can answer the question of the Shakespearean Juliet: Wherefore art thou ROM(e)O1? ROM(e)O is there to couple ROS to mitochondrial shape!

The protein ROMO1 was not unknown: This small mitochondrial protein shows increased abundance in several tumor cell lines (12), and its role in mitochondrial oxidative stress—which affected proliferation (13), senescence, (14) and cell death (15)—was well characterized. The high-content imaging screening set up by Norton et al. (11) identified a previously unknown phenotype of mitochondrial fragmentation in cells lacking ROMO1. By a thorough biochemical characterization, Screaton and colleagues demonstrate that this protein displays a classical redox sensor module formed by two conserved cysteine residues (Cys15 and Cys79). In an oxidizing environment, an intermolecular disulfide bond caused ROMO1 oligomerization, inactivated the protein, and impaired mitochondrial fusion. Of note, even if Romo1 is the mammalian homolog of a component of the cristae junction organizing complex Minos (also known as Mitos) (16), its effects on mitochondrial morphology appear to be independent from the components of this complex and are instead mediated by OPA1. OPA1 is a master regulator of the mitochondrial fusion process and also of cristae shape and remodeling (8). Mitochondrial cristae are the site of respiration and, hence, the reservoir of cytochrome c, a key molecule involved in the intrinsic apoptotic pathway; their remodeling is required to release the bulk of cytochrome c and to fully activate apoptosis (17). OPA1 oligomers stabilize cristae morphology and prevent cristae remodeling; indeed, they are early targets during apoptosis to remodel cristae, release cytochrome c, and impair mitochondrial function (18). Norton et al. demonstrate that ROMO1 modulates cristae shape: ROMO1 loss induces OPA1 cleavage, impairs OPA1 oligomerization, causes cristae remodeling, and augments sensitivity toward apoptosis (Fig. 1).

Fig. 1. ROMO1-mediated changes in cristae shape.

The cartoon depicts how Romo1 inactivation causes Opa1 cleavage, thereby affecting Opa1 oligomerization and enhancing cristae remodeling that enables the release of cytochrome c (Cyt C).


The role of Opa1-dependent cristae remodeling in apoptosis is increasingly appreciated. However, several points remain unclarified, including the relation between cristae and ROS production. The work by Screaton and colleagues helps to solve this long-standing issue by identifying a molecule involved in ROS production and, at the same time, in translating the redox status into mitochondrial morphological alterations. When cristae are remodeled, not only are cells more prone to apoptosis, mitochondrial respiratory chain supercomplexes are also disassembled (19), likely favoring a vicious circle that increases ROS production. Therefore, the finding that many types of tumor show increased abundance of ROMO1 is not surprising. Targeting ROMO1 could thus be beneficial in sensitizing cancer cells to cristae remodeling–dependent cell death while at the same time interrupting the production of ROS that participate in signaling pathways supporting cell proliferation. The work by Norton et al. also indicates the power of high-content screening to identify previously unknown players in mitochondrial morphology, at least at the regulatory level. It is expected that the analysis of the other candidates identified by this screen will increase our knowledge of the integration between mitochondrial morphology and cellular physiology.


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