Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria

The inside of a human cell is divided into compartments called organelles, which are surrounded by membranes. Each organelle plays a specific role in keeping the cell healthy and also has unique mix of molecular markers on its surface. These markers allow other molecules to identify the different organelles, meaning that specific organelles can communicate with each other and coordinate their activities. One way that organelles can do this is via so-called membrane contact sites, which are small areas where the compartments’ outer membranes come close together.

Mitochondria are organelles that release energy inside human cells. These compartments also work to keep the levels of toxic chemicals called reactive oxygen species in the cell within a safe range. This is important because cells can die if these levels become too high – a state known as oxidative stress. Mitochondria also communicate with other organelles called endosomes, which receive materials from the cell surface, sort and direct them to different destinations throughout the cell.

In many diseases affecting the nervous system, the mitochondria and endosomes in nerve cells do not work properly. These cells also have higher than normal levels of oxidative stress. Hsu et al. therefore wanted to find out if mitochondria and endosomes worked together to help cells to cope with this kind of stress.

Hsu et al. triggered oxidative stress in human cancer cells by exposing them first to a dye that stained the mitochondria and then to intense light. In stressed cells, a subset of endosomes called early endosomes formed many more membrane contact sites with mitochondria than in non-stressed cells. At the same time, the protein Rab5, usually found on early endosomes, relocated to the surface of mitochondria. Human cells previously engineered to produce larger than normal amounts of Rab5 were also more likely to survive oxidative stress. These experiments suggested that early endosomes cooperate with mitochondria, via Rab5, to protect cells from oxidative stress.

So, how is Rab5 relocated to mitochondria? Hsu et al. searched for activators of Rab5 and found that Alsin also migrated to mitochondria in stressed cells. The gene for Alsin is also mutated in amyotrophic lateral sclerosis (ALS), a degenerative nerve disorder that remains poorly understood. Next, Hsu et al. deleted the gene for Alsin from human stem cells growing in the laboratory and coaxed these cells into becoming nerve cells. Experiments with these cells showed that the absence of Alsin prevented Rab5 from moving to the mitochondria. Nerve cells lacking Alsin were also more susceptible to oxidative stress than normal cells.

Together, these findings show that early endosomes work with mitochondria to sense and ward off oxidative stress. They also reveal an unexpected connection between this process and a gene mutated in ALS. Further experiments are now needed to explore if problems with endosomes or mitochondria, and specifically with molecules like Alsin and Rab5, are responsible for other neurodegenerative disorders, like Parkinson’s disease and Huntington’s disease.

Mitochondria, the organelle for cellular metabolism and ATP production, play an essential role in a number of other cellular processes such as calcium signaling, lipid synthesis and trafficking, metabolite transport, apoptosis, and reactive oxygen species (ROS) production in the cell (Mesmin, 2016; Ott et al., 2007; Rizzuto et al., 2012). Many of these processes necessitate communication with other cellular compartments. For example, membrane contact sites (MCS) between endoplasmic reticulum (ER) and mitochondria are important for Ca²⁺ and lipid transfer (de Brito and Scorrano, 2008), mitochondria fission (Friedman et al., 2011), and regulation of apoptosis (Prudent et al., 2015). Lipid droplets and peroxisomes interact with mitochondria to regulate fatty acid oxidation (Cohen et al., 2014; Pu et al., 2011). Oxidized and damaged proteins can be selectively delivered to peroxisomes and lysosomes via mitochondrial-derived vesicles (Sugiura et al., 2014). These examples demonstrate an extensive functional interplay between organelles, either directly via MCS and/or indirectly via vesicular intermediates. However, the underlying molecular mechanisms remain poorly understood and, in particular, the functional relationship between mitochondria and the endocytic system is largely unexplored.

The endocytic pathway is responsible for maintaining cellular homeostasis by internalizing, sorting, recycling and/or degrading distinct types of cargo molecules (Huotari and Helenius, 2011). Rab GTPases serve as molecular signatures on endosomes, regulating their biogenesis and functions (Pfeffer, 2017; Zerial and McBride, 2001; Zhen and Stenmark, 2015). Ligand-receptor complexes at the plasma membrane (PM) are internalized into early endosomes (EE) marked by small GTPase Rab5, followed by either recycling to the PM via Rab4 and Rab11-positive recycling endosomes (RE), or routed to late endosomes (LE) and lysosomes for degradation. The latter process occurs via the conversion of Rab5-positive EE into Rab7-positive LE (de Renzis et al., 2002; Rink et al., 2005; Sönnichsen et al., 2000; Ullrich et al., 1996). Rab proteins can thus dynamically associate with the membranes, conferring functional plasticity to organelles. On these endosomal membranes, Rab proteins recruit a plethora of effectors for membrane tethering and fusion, cargo sorting and signaling (Sorkin and von Zastrow, 2009; Stenmark, 2009; Zerial and McBride, 2001). For example, EEA1 is a dimeric coiled-coiled Rab5 effector protein that tethers two vesicles to allow efficient fusion between Rab5-harbouring membranes (Murray et al., 2016; Ohya et al., 2009). Other Rab5 effectors such as APPL1 are involved in regulating metabolic and inflammatory responses (Schenck et al., 2008; Wen et al., 2010). Rab activation, and thus stabilization after recruitment, on the membrane requires guanine nucleotide exchange factors (GEFs) (Blümer et al., 2013). Rab5 GEFs constitute a family of VPS9 domain-containing proteins, including Rabex-5 (Horiuchi et al., 1997), RME-6 (Sato et al., 2005), amyotrophic lateral sclerosis protein 2 (ALS2/Alsin) (Otomo et al., 2003), and mammalian Ras and Rab interactor 1, 2, 3 (Rin1-3) (Hu et al., 2005). The rationale behind this complexity is that Rab5 must be specifically regulated by different GEFs in space and time. In this respect, the function of many Rab5 GEFs remains unclear.

Physical interactions between the endosomal machinery and mitochondria serve important functions in cell homeostasis, repair and apoptosis. For example, transfer of iron (Das et al., 2016; Sheftel et al., 2007) and cholesterol (Charman et al., 2010) from endosomes to mitochondria is mediated by physical interactions between the two organelles. Another classical example of mitochondria-endolysosome interactions is autophagy. Autophagy is a clearance mechanism whereby cells identify defective organelles following damage or stress, and eliminate them via the formation of an autophagosome and subsequent fusion with lysosomes (Mizushima and Levine, 2010). The mechanism of degrading mitochondria has been termed macroautophagy or mitophagy. Intriguingly, the expression of pro-apoptotic factors such as canonical BH3-only proteins drive Rab5- and Rab7-positive endolysosomes into inner mitochondrial compartments via a pathway that appears to differ from autophagy/mitophagy (Hamacher-Brady et al., 2014). Interestingly, our previous conducted genome-wide RNAi screen of endocytosis (Collinet et al., 2010) revealed that ~8% of the hit genes had mitochondrial-related functions, pointing at hitherto unexplored molecular connections between the endosomal system and mitochondria. This led us to hypothesize that other mitochondrial functions may be regulated by endocytic components.

Here by exploring the interactions between EE and mitochondria, we unexpectedly found that upon laser- or chemically induced oxidative stress in mammalian cells, mitochondria outer membrane permeabilization (MOMP) releases cytochrome c, and concomitantly, triggers the assembly of the Rab5 machinery on mitochondria, in a process which is reversible and independent of mitophagy. Remarkably, we found that the Rab5 GEF responsible for Rab5 activation is ALS2/Alsin, which is necessary for efficient Rab5 recruitment to mitochondria. Our findings suggest that the Rab endocytic machineries interact with mitochondria during oxidative stress as a cytoprotective mechanism, with important implications for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

We discovered a novel cytoprotective mechanism during oxidative stress entailing the translocation of Rab5 from EE to mitochondria. Interestingly, the activation of Rab5 requires Alsin, which has been implicated in early onset ALS. Our results provide an unexpected mechanistic link between the endosomal system and mitochondria that could be of primary importance for understanding the mechanistic cause of ALS and other neurodegenerative diseases.

Different nutrient or environmental perturbations can affect mitochondria morphology and metabolic activities such as oxidative phosphorylation and programmed cell death (Galloway and Yoon, 2013). Mitochondria can elicit adaptive responses to oxidative stress that may lead to hypoxia adaptation, inflammation, or programmed cell death (Sena and Chandel, 2012). Our findings suggest that the endocytic system is a primary responder to mitochondria under oxidative stress. Laser- or exogenous ROS (e.g. H₂O₂)-induced damage causes MOMP, mitochondrial swelling, and release of cytochrome c, leading to caspase activation and apoptosis. Under these conditions, the endosomal system appears to rapidly respond to damaged mitochondria through a rescue pathway, which results in the recruitment of Alsin and Rab5 to mitochondria, inhibition of cytochrome c release, decrease in mitochondrial oxygen consumption and hence, increased overall cell viability (Figure 12). In the course of this study, a mitochondrial clearance mechanism was reported where Rab5-positive EE sequester mitochondria via the ESCRT machinery when cells are treated with the proton uncoupler FCCP (Hammerling et al., 2017), an analog of CCCP. Our mechanism appears to be distinct from this as well as the canonical autophagic/mitophagic mechanisms. First, we did not observe the engulfment of mitochondria into Rab5-positive EE but rather, the recruitment of Alsin, Rab5, and Rabenosyn-5 on mitochondria, as well as an increase in early endosomal-mitochondrial MCS in response to stress. This is also distinct from the intra-mitochondrial recruitment of Rab5 and endo-lysosomes upon over-expression of the apoptotic factors (Hamacher-Brady et al., 2014). Second, we did not observe engulfing membraneous structures around stressed mitochondria nor upon CCCP treatment. One explanation could be the use of different cell types and the lower concentration of CCCP employed in our experiments. Third, the recruitment of Rab5 to damaged mitochondria occurs rapidly, that is within min, well preceding any autophagic components that we analyzed in this study. We found that autophagy is restricted to only a subset of small mitochondrial fragments that are LC3⁺, whereas the majority are devoid of known autophagic markers such as Parkin, LC3 and Lamp1. We could not rule out that mitochondrial clearance mechanism may still be activated at a later time. However, our data with H₂O₂ show that the mechanism described here is reversible (Figure 8) and argue for a mitochondrial-protective role rather than a degradative process. In fact, the reversal and recovery of cells from late-stage apoptosis (i.e. following cytochrome c release and caspase activation) have recently been reported in multiple cells lines including HeLa cells and brain cells in a process called ‘anastasis’ (Sun et al., 2017; Tang et al., 2012), suggesting that this may be a general mechanism to cope with cellular stress. We attempted to track the fate of individually damaged mitochondria in a localized region after laser treatment (data not shown), but the continuous photoirradation required to achieve a high spatio-temporal resolution also led to a quick decrease in MitoTracker Red signal and undesirable additional stress to the cell over time, preventing us from determining its precise outcome. The loss of Mito-Red signal is likely due to MOMP, as evident by the release of cytochrome c, and not a result of mitochondrial clearance because the outer mitochondrial membrane can be stained by TOM20 and visualized by the presence of Rab5 ring-like formation.

Figure 12

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Which molecular mechanism is responsible for the dissociation of Rab5 from EE and its recruitment to mitochondria? On EE, the levels of Rab5 depend on the equilibrium between the cytosolic pool of Rab5 complexed to Rab GDI and the membrane-associated pool sustained by the Rabex-5/Rabaptin-5 complex and a plethora of Rab5 effectors (Del Conte-Zerial et al., 2008; Lippé et al., 2001; Zerial and McBride, 2001; Zhang et al., 2014). Prior studies have shown that such equilibrium, and consequently endocytic trafficking, is adaptive to stress and apoptotic signal. For example, Rabaptin-5 is selectively cleaved by caspase-3 during apoptosis, thus affecting its interaction with Rab5 and reducing the overall endocytic capacity (Cosulich et al., 1997; Swanton et al., 1999). The activation of p38 MAPK by H₂O₂ also stimulates the formation of the GDI:Rab5 complex, thus favoring the extraction of Rab5 from the early endosomal membrane (Cavalli et al., 2001). In addition, p38 MAPK modulates the endosomal function via phosphorylation and membrane association of Rab5 effectors (Macé et al., 2005). Such a mechanism may account for the mobilization of Rab5 from the endosomal membrane, which is suggested by increased in cytosolic Rab5 and decreased colocalization of Rab5 with the endosomal EEA1 (Figure 6A–C). These phenotypes correlated to a defect in endosomal sorting (Figure 1E) and a block in transferrin uptake (Figure 6D,E), which may be yet another protective mechanism in order to avoid iron overload and toxicity associated with neurodegeneration (Núñez et al., 2012). Interestingly, hippocampal HT-22 neurons exposed to excess iron exhibit mitochondrial fragmentation and a decrease in cell viability (Park et al., 2015). The metabolic effect of H₂O₂ on OCR is intriguing. Mitochondria require oxygen to produce ATP to drive energy-consuming reactions (Bratic and Trifunovic, 2010). The observed decrease in OCR (Figure 5E) may serve to lower cellular respiration and prevent further ROS production.

If the stress response triggers solubilization of Rab5 from EE, then it must also catalyze the activation of Rab5 on mitochondria. We discovered that this step depends on Alsin. The C-terminal VPS9 domain of Alsin has GEF activity towards Rab5, and plays a role in Rab5 endosomal localization and dynamics (Otomo et al., 2003; Topp et al., 2004). However, the physiological role of Alsin with respect to Rab5 and endosomal activity has remained somewhat mysterious. At steady state, Alsin is mainly cytosolic with a fraction localizing to vesicular-like structures (Figure 10—figure supplement 1C) (Millecamps et al., 2005). In stress-induced conditions, however, Alsin re-localizes to mitochondria. The N-terminal RLD of Alsin has been shown to exhibit an autoinhibitory effect on its VPS9 domain (Otomo et al., 2003). We posit that mitochondrial-induced stress triggers structural changes in the protein, releasing the autoinhibitory effect of RLD, thereby exposing the VSP9 domain for Rab5 activation and recruitment. Alsin was required for Rab5 translocation to mitochondria as this was severely diminished in Alsin^-/- iPS-sMN cells. The presence of (low levels) Rabex-5 on mitochondria (Figure 10A,C) detected in HeLa cells suggests that other GEFs may contribute to some Rab5 activation, depending on the cell types, but cannot fully compensate for the loss of Alsin function. A homologous gene, ALS2CL, containing only the carboxyl-terminal half of ALS2, may also play a role by specifically binding to Rab5 and forming a homodimer with the full-length Alsin to membranous compartments (Hadano et al., 2004; Suzuki-Utsunomiya et al., 2007).

What is the function of the assembly of Rab5 and Rab5 machinery (Alsin and Rabenosyn-5) on mitochondria besides its protective role? The stress response triggers remodeling of mitochondria to confer molecular features characteristic of the endocytic system. The Rab5 machinery may be used to bring mitochondria in close proximity to EE and form MCS (Figure 1). These MCS may mediate the transfer of lipids and metabolites (Helle et al., 2013), or involve in ‘patching’ up mitochondrial wounds by recruiting the ESCRT machinery for closure, or other endomembranes for fusion, both of which are observed in the PM-repair response (Jimenez et al., 2014; Reddy et al., 2001). Worth noting from our EM study, we observed ER-like membranous structure in contact with stressed mitochondria (Figure 3C) and considering the role of ER-mitochondria contacts in Ca²⁺-regulated apoptosis (Pinton et al., 2008), one may postulate that an orchestrated three-way organelle crosstalk exists.

Considering that Rab5 is necessary for the biogenesis of the endolysosomal system (Zeigerer et al., 2012), the Rab5 translocation may be a priming step of a stress response pathway that subjects mitochondria to interact with the entire endolysosomal system, in order to modulate the mitochondrial apoptotic potential. One quality control mechanism is the formation of mitochondrial-derived vesicles (MDVs), which are involved in the transport of oxidized or damaged cargo to LE and lysosomes for degradation (Soubannier et al., 2012). This process depends on PINK1/Parkin (McLelland et al., 2014), but can also occur independently (Matheoud et al., 2016). Rab5 may play a role in MDV formation, although we could not detect vesicle budding events in our experimental conditions. Once recruited onto mitochondria, Rab5 activity may not be limited to the recruitment of its effectors, but initiate a more extensive endosomal Rab cascade via the Rab coupling/conversion mechanism. On EE, Rab5 interacts with divalent effectors, coupling its activity to other Rab proteins (e.g. Rab4, Rab11) that are required for receptor recycling (de Renzis et al., 2002; Vitale et al., 1998). Rab5 also initiates the activation of Rab7, resulting in the conversion of EE into LE (Rink et al., 2005). The Rab coupling/conversion may also be initiated on the mitochondria. Therefore, it is possible that the mitochondria-endosome MCS may evolve over time leading to a Rab7-dependent mitophagic pathway (Jimenez-Orgaz et al., 2018), the engulfment of mitochondria by the EE (Hammerling et al., 2017), or conventional autophagic processes (Ao et al., 2014; Stolz et al., 2014). Future work exploring the dynamics of other endosomal Rab GTPases in relation to Rab5 will be necessary to elucidate the precise role of the endosomal system on mitochondria.

The physiological role of Alsin, although elusive, has been linked to both endosomes and mitochondria. Cultured hippocampal neurons from Alsin knockout mice display an accumulation of enlarged Rab5 endosomes and a reduced endosomal motility (Lai et al., 2009). Mutational and linkage analysis of Alsin from human patients show that the VPS9 domain is critical for Alsin function (Daud et al., 2016; Verschuuren-Bemelmans et al., 2008). A recent EM study on the corticospinal motor neurons (CSMN) from Alsin KO mice reveals a selective morphological defect in mitochondria with enlarged core and broken cristae (Gautam et al., 2016). Interestingly, WT vs Alsin KO CSMN show no change in Parkin expression, suggesting that mitophagy does not play a major role (Gautam et al., 2016). We postulate that the pathological condition of mitochondrial defects in Alsin KO cells is related to a deficiency in Rab5 recruitment to mitochondria, thereby leading to a decline in protection from ROS and oxidative stress associated with aging. In ALS patients, motor neurons likely accumulate more damaged mitochondria as age progresses, which eventually become an overburden for cells.

The primary cause for ALS is still unclear, but oxidative stress is considered to be a major contributor. Mutations in the antioxidant enzyme, superoxide dismutase 1 (SOD1), are associated with motor neuron degeneration. In mouse models, an accumulation of the SOD1 mutant proteins results in mitochondrial swelling and increased oxidative damage (Jaarsma et al., 2001). Interestingly, loss of Alsin in the mutant SOD1 transgenic mice exacerbates and accelerates disease progression (Hadano et al., 2010). These studies, along with our findings, corroborate the protective role of Alsin during oxidative stress. The mechanistic link between Rab5 and Alsin may present a general or related mechanism in other neurodegenerative diseases. In Parkinson disease, the most common mutation in the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein leads to a hyper-activation of the kinase domain, resulting in hyper-phosphorylation of a number of Rab GTPase substrates including Rab5 (Steger et al., 2017; Steger et al., 2016). This may present yet another mechanism of regulating Rab5 localization and function on mitochondria. Future work using different neurodegenerative disease models in differentiated human neurons will provide deeper insights into the disease etiology.

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Author details

1. FoSheng Hsu

   Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8486-7311

2. Stephanie Spannl

   Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

   Contribution

   Data curation, Formal analysis, Methodology, Writing—review and editing

   For correspondence

   spannl@mpi-cbg.de

   Competing interests

   No competing interests declared

3. Charles Ferguson

   Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia

   Contribution

   Data curation, Investigation, Methodology

   For correspondence

   c.ferguson@imb.uq.edu.au

   Competing interests

   No competing interests declared

4. Anthony A Hyman

   Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

   Contribution

   Supervision, Writing—review and editing

   For correspondence

   hyman@mpi-cbg.de

   Competing interests

   Reviewing editor, eLife

5. Robert G Parton

   1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
   2. Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Australia

   Contribution

   Data curation, Investigation, Methodology, Writing—review and editing

   For correspondence

   r.parton@imb.uq.edu.au

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7494-5248

6. Marino Zerial

   Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

   Contribution

   Conceptualization, Supervision, Funding acquisition, Investigation, Writing—original draft, Writing—review and editing

   For correspondence

   zerial@mpi-cbg.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7490-4235

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