Mutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.

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 ▲]

Does uncoupling protein 2 expression qualify as marker of disease status in LRRK2-associated Parkinson's disease?

in Antioxidants & redox signaling (2014), 20(13), 1955-60

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of late-onset Parkinson's disease (PD). However, the penetrance of the disease is below 50% at 60 years of age ... [more ▼]

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of late-onset Parkinson's disease (PD). However, the penetrance of the disease is below 50% at 60 years of age. LRRK2 is associated with the mitochondrial membrane, and mutant forms impair the function of the organelle and autophagosome clearance in human cells, including induced pluripotent stem cell-derived neurons. Elevated expression of uncoupling proteins has been identified as the cause of mitochondrial depolarization in human fibroblasts with G2019S LRRK2. To identify factors that contribute to the penetrance of LRRK2 mutations, we studied respiratory chain function, markers of mitochondrial uncoupling, oxidative stress, and autophagy in fibroblasts from affected and unaffected carriers of the G2019S mutation. Independent of disease status, all mutation carriers showed reduced mitochondrial membrane potential, increased proton leakage, and more fragmented mitochondria. However, a significant increase in the expression of uncoupling protein 2 (UCP2) was only detected in affected individuals with the G2019S mutation in LRRK2. Since oxidative stress and autophagic markers were selectively increased in some of the PD patients, we hypothesize that UCP2 expression is upregulated in response to elevated reactive oxygen species generation in affected mutation carriers and that UCP2 mRNA levels might, therefore, serve as markers of disease status in LRRK2-associated PD. [less ▲]