MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

Nemani, Neeharika; Carvalho, Edmund; Tomar, Dhanendra; Dong, Zhiwei; Ketschek, Andrea; Breves, Sarah L.; Jaña, Fabián; Worth, Alison M.; Heffler, Julie; Palaniappan, Palaniappan; Tripathi, Archana; Ramasamy, Subbiah; Riitano, Massimo F.; Seelam, Ajay; Mussack, Thomas; Itoh, Kie; Meng, Shuxia; Sesaki, Hiromi; Craigen, William J.; Rajan, Sudarsan; Shanmughapriya, Santhanam; Caplan, Jeffrey; Prosser, Benjamin L.; Gill, Donald L.; Stathopulos, Peter B.; Gallo, Gianluca; Chan, David C.; Mishra, Prashant; Madesh, Muniswamy

doi:10.1016/j.celrep.2018.03.098

Cited by 87 publications

(96 citation statements)

References 48 publications

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“…This mechanism provides a link between environmental/intracellular stimuli and mitochondrial morphofunction. With respect to calcium homeostasis, mitochondria can undergo ''mitochondrial shape transition'' (MiST), which is distinct from mitochondrial fission/swelling and mediated by the mitochondrial Rho GTPase 1 (MIRO1) (280). MiST was induced by increased calcium levels in the cytosol, but not by mitochondrial calcium uptake by the mitochondrial calcium uniporter (MCU).…”

Section: Opa1mentioning

confidence: 99%

Mitochondrial Morphofunction in Mammalian Cells

Bulthuis

Adjobo‐Hermans

Willems

et al. 2019

Antioxidants & Redox Signaling

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Significance: In addition to their classical role in cellular ATP production, mitochondria are of key relevance in various (patho)physiological mechanisms including second messenger signaling, neuro-transduction, immune responses and death induction. Recent Advances: Within cells, mitochondria are motile and display temporal changes in internal and external structure (''mitochondrial dynamics''). During the last decade, substantial empirical and in silico evidence was presented demonstrating that mitochondrial dynamics impacts on mitochondrial function and vice versa. Critical Issues: However, a comprehensive and quantitative understanding of the bidirectional links between mitochondrial external shape, internal structure and function (''morphofunction'') is still lacking. The latter particularly hampers our understanding of the functional properties and behavior of individual mitochondrial within single living cells. Future Directions: In this review we discuss the concept of mitochondrial morphofunction in mammalian cells, primarily using experimental evidence obtained within the last decade. The topic is introduced by briefly presenting the central role of mitochondria in cell physiology and the importance of the mitochondrial electron transport chain (ETC) therein. Next, we summarize in detail how mitochondrial (ultra)structure is controlled and discuss empirical evidence regarding the equivalence of mitochondrial (ultra)structure and function. Finally, we provide a brief summary of how mitochondrial morphofunction can be quantified at the level of single cells and mitochondria, how mitochondrial ultrastructure/volume impacts on mitochondrial bioreactions and intramitochondrial protein diffusion, and how mitochondrial morphofunction can be targeted by small molecules.

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Section: Opa1mentioning

confidence: 99%

Mitochondrial Morphofunction in Mammalian Cells

Bulthuis

Adjobo‐Hermans

Willems

et al. 2019

Antioxidants & Redox Signaling

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“…Finally, beyond the transport of mitochondria, the shape of mitochondria is also regulated by Ca 2+ . A recent study links Miro's calcium‐binding capacity to mitochondrial shape transition that occurs to differentiate mitochondria between long networked organelles that are more efficient at energy production and shorter, round organelles that are frequently associated with pathological states or apoptotic signals . Live‐cell imaging revealed that mitochondrial shape change occurred prior to the opening of the permeability transition pore, mitochondrial swelling, and calcium uptake through the mitochondrial calcium uniporter.…”

Section: Miro: Allosteric Regulation With Wide‐spread Cellular Conseqmentioning

confidence: 99%

Miro: A molecular switch at the center of mitochondrial regulation

et al. 2020

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The orchestration of mitochondria within the cell represents a critical aspect of cell biology. At the center of this process is the outer mitochondrial membrane protein, Miro. Miro coordinates diverse cellular processes by regulating connections between organelles and the cytoskeleton that range from mediating contacts between the endoplasmic reticulum and mitochondria to the regulation of both actin and microtubule motor proteins. Recently, a number of cell biological, biochemical, and protein structure studies have helped to characterize the myriad roles played by Miro. In addition to answering questions regarding Miro's function, these studies have opened the door to new avenues in the study of Miro in the cell. This review will focus on summarizing recent findings for Miro's structure, function, and activity while highlighting key questions that remain unanswered.

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“…Miro1 acts as sensor for cytosolic calcium levels [8,28,29]. Accordingly, we recently showed that patient-derived fibroblasts expressing mutant Miro1 proteins display a decreased capacity to buffer cytosolic calcium after inhibition of ER calcium ATPase by thapsigargin treatment [10].…”

Section: Increased Calcium Stress Is a Shared Phenotype Across Differmentioning

confidence: 99%

“…Interestingly, Miro1 plays a central role in a number of molecular and organellar pathways, which are affected in PD. Via its interaction with PINK1, Parkin and LRRK2 [2], Miro1 interferes with mitochondrial quality control and MERCs [5,8,9]. Having access to fibroblasts from PD patients carrying different Miro1 mutations, we explored the role of Miro1 at MERCs in more detail.…”

Section: Introductionmentioning

confidence: 99%

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Berenguer-Escuder

Großmann

Massart

et al. 2019

JCM

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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.

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MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress

Cited by 87 publications

References 48 publications

Mitochondrial Morphofunction in Mammalian Cells

Mitochondrial Morphofunction in Mammalian Cells

Miro: A molecular switch at the center of mitochondrial regulation

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

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