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See detailVariants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients
Berenguer, Clara UL; Grossmann, Dajana; Massart, François UL et al

in Journal of Clinical Medicine (2019)

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD ... [more ▼]

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. [less ▲]

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See detailPATHOGENIC ROLE OF PARKINSON’S DISEASE-ASSOCIATED MIRO1 MUTATIONS IN THE MITOCHONDRIAL-ENDOPLASMIC RETICULUM INTERPLAY
Berenguer, Clara UL

Doctoral thesis (2019)

Parkinson´s disease (PD) is a chronic neurodegenerative disorder, in which only 5-10% of the cases are caused by genetic mutations. One of the main pathological hallmarks of PD is the loss of midbrain ... [more ▼]

Parkinson´s disease (PD) is a chronic neurodegenerative disorder, in which only 5-10% of the cases are caused by genetic mutations. One of the main pathological hallmarks of PD is the loss of midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of diseased brains. These DA neurons require large amounts of energy for the maintenance of their pace-making activity and their complex dendritic and axonal arborizations, features that force them to rely on a fully functional mitochondrial network. In this regard, mitochondrial dyshomeostasis is a central factor in PD pathophysiology. Mitochondria are considered the powerhouse of the cells, and they are extremely dynamic organelles that are distributed throughout the entire neuronal body to meet the cellular energy demands. The maintenance of mitochondrial function requires their interaction with other cellular organelles, in particular, the endoplasmic reticulum (ER). Overwhelming evidence indicates that the mitochondrial-ER interface is a potential target of growing importance for the investigation of PD. Several PD-related proteins were found to be involved in the structural maintenance and signaling regulation of mitochondrial-ER contact sites (MERCs). In recent years, myriad studies have identified the mitochondrial GTPase Miro1 as a crucial player in PD pathology. Miro1 protein is not only an adaptor for mitochondrial transport, but also acts as a cytosolic calcium sensor and as an ubiquitination target for the mitochondrial quality control machinery. Moreover, Miro1 can localize to MERCs, where it functions as a regulator of the calcium exchange between both organelles. To date, no genetic link between Miro1 and PD has been identified, and the influence of Miro1 in the regulation of MERCs within the context of neurodegeneration is still underestimated. This current study explored the damaging effect of novel PD-associated heterozygous mutations in RHOT1, the gene encoding Miro1 protein, in a diseased genetic background. We first obtained skin fibroblasts from the affected PD patients harboring Miro1 mutations, which we further differentiated into iPSC-derived neurons. The characterization of the mutations in both patient-derived cellular models unveiled important impairments in mitochondrial calcium homeostasis and sensitivity to calcium stress, associated with alterations in the abundance and functionality of the MERCs. Consequently, downstream pathways to these mechanisms were affected, such as autophagy flux and mitochondrial clearance. From our results, we can conclude that PD-associated mutant Miro1 leads to crucial alterations in MERCs, consequently affecting downstream mechanisms such as calcium homeostasis and mitophagy. These dysregulations might lead to an increased sensitivity to stress and finally cell death. Our findings strongly support the key role of MERCs in the progress of neurodegeneration and establish RHOT1 as a rare genetic risk factor in PD. [less ▲]

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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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