Bartolome F, Wu HC, Burchell VS, Preza E, Wray S, Mahoney CJ, Fox NC, Calvo A, Canosa A, Moglia C, Mandrioli J, Chiò A, Orrell RW, Houlden H, Hardy J, Abramov AY, Plun-Favreau H.
Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.
Neuron. 2013 Apr 10;78(1):57-64.
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The studies by Kim and Bartolome represent two sides of the same coin and provide solid evidence of mitochondrial involvement in VCP-related diseases. Kim et al. provide a detailed, mechanistic analysis of how VCP mutations impair mitophagy. Their results show that VCP is recruited to dysfunctional mitochondria that were ubiquitinated by parkin. The mitophagy pathway delineated by these studies is that mitochondrial dysfunction leads to mitochondrial relocalization of PINK1, in turn recruiting parkin and VCP.
The Bartolome paper is more descriptive and shows that the VCP mutations, as well as VCP loss of function, lead to mitochondrial uncoupling and subsequent loss of ATP production.
How could these two studies be linked? In the picture described by Kim and collaborators, it would be quite expected that the loss of VCP, or its mutations, leads to the accumulation of dysfunctional mitochondria, which are unable to be recycled, and, thus, a global loss of mitochondrial function. VCP-mediated disease would therefore be, at least partially, the result of a traffic jam of dysfunctional mitochondria. This provides a conceptual framework to understand why VCP mutant cells lose mitochondrial potential and the capacity to synthesize ATP. In all, the two papers nicely complement each other and provide very convincing evidence that VCP mutations alter mitochondrial function through dysfunctional recycling of abnormal mitochondria.
There are several questions raised by these studies. First, what is the disease relevance of mitochondrial dysfunction towards IBM-PFD and ALS? Kim et al. show that overexpression of mutant VCP in flies leads to motor neuron and muscle phenotypes, as well as mitochondrial abnormalities, but it remains unknown whether the mitochondrial phenotype is indeed the cause of the neurodegenerative and myopathic phenotype. As stated by the authors in their discussion, the "mitophagy-related" function of VCP is not the only VCP function altered by mutations. The critical function(s) altered by the mutations that cause the phenotype still need to be defined. Second, these papers add to the puzzling diversity of neurodegenerative diseases involving the mitochondrial quality control pathway. Despite the fact that PINK1, parkin, mitofusins, OPA1, DRP1, and now VCP are all involved to some extent in the mitochondrial quality pathway, mutations in these genes lead to a vast array of previously unlinked clinical phenotypes, from Parkinson's disease to hereditary neuropathies, and from ALS and FTD to IBM and myopathies. Dissecting how a seemingly ubiquitous mitochondrial defect leads to a cell-type selective degeneration remains a challenge. Conversely, similar VCP mutations are able to lead to completely different clinical phenotypes. Whether a second hit, either genetic or environmental, might lead VCP mutations to trigger IBM-PFD rather than ALS remains to be determined.
The AAA ATPase VCP serves as a vital nanomachine by regulating ubiquitinated substrates for proteasomal degradation. With the discovery of VCP missense mutations that link to inherited disorders such as IBM-PFD, ALS, and FTD, along with the pathological appearance of this protein in other neurological disorders, it seems that this evolutionary conserved protein may be an important clue in solving a possible convergent pathogenic mechanism among many diseases.
In the Neuron papers, the authors report that control of mitochondrial integrity has a lot to do with VCP. Dr. Taylor’s group used both genetic and cell-based analyses to show that VCP may be involved in monogenic PD pathogenesis through the degradation of the mitochondrial membrane protein mitofusin. Earlier reports using fly PD models have demonstrated that two familiar PD factors, PINK1 and parkin, can directly modulate mitochondrial dynamics. Others also revealed that VCP might do the same. Another important thing to note: This study nicely showed that sequential recruitment of parkin, followed by VCP, to the damaged mitochondria may be important for keeping these energy factories functioning properly. Although how this mechanism plays out remains to be answered, these data certainly fit into the notion that mitochondria dysfunction may be a key to PD pathogenesis.
The second paper, reported by Bartolome et al., showed that either knocking down VCP or expressing IBM-PFD-linked disease mutants could induce mitochondrial uncoupling, which resulted in reduced ATP levels. Part of their results are consistent with our earlier report showing that flies expressing pathogenic VCP alleles have reduced cellular ATP. However, given that a number of reports demonstrated VCP disease mutations could have normal or higher-than-normal ATPase activity, it is puzzling how the knockdown of this ATPase would impair mitochondrial function similarly to those disease alleles found in patients. Nevertheless, this interesting finding certainly opens a new window to further delineate VCP-associated energy metabolism. Overall, both studies attest to the idea that balanced energy production and expenditure in postmitotic cells, such as neurons, are truly essential for maintaining a healthy brain.
The link between these two papers is that VCP mutations have deleterious effects on mitochondria. However, the two groups approach this from different directions. Plun-Favreau et al. studied mitochondrial function in fibroblasts and show that there is uncoupling, which, as expected, reduces membrane potential and ATP production, but increases O2 consumption. This would be expected to make neurons and other cells more vulnerable to other insults having effects on bioenergetics such as ischemia or pesticide exposure. The second paper by Taylor et al. provides strong evidence for an important role of VCP in mitophagy. It shows that VCP can complement PINK1 deficiency but not parkin deficiency, since parkin-mediated ubiquitination is required to recruit VCP to damaged mitochondria and for degradation of mitofusins.
There were prior data showing links to mitophagy and abnormal mitochondria in mouse VCP knock-in models, but these data are much more definitive, particularly the studies of Taylor and colleagues, which provide strong genetic evidence. How do we relate this to brain, spinal cord, and muscle? That is not too hard, since both neurons and muscle cells are postmitotic and consume large amounts of energy.
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