A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Li, Li; Conradson, Devon M; Bharat, Vinita; Kim, Min Joo; Hsieh, Chung-Han; Minhas, Paras; Papakyrikos, Amanda M.; Durairaj, Aarooran Sivakumaran; Ludlam, Anthony V.; Andreasson, Katrin I.; Partridge, Linda; Cianfrocco, Michael A.; Wang, Xinnan

doi:10.1038/s42255-021-00443-2

Cited by 32 publications

(48 citation statements)

References 67 publications

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“…The actin cytoskeleton and myosin proteins also play a role in mitochondrial trafficking and anchoring, although this is believed to support short movements (Sheng, 2014). The microtubule motor proteins are linked to mitochondria via the TRAK1/2 (Milton) adapter proteins which connect to the outer mitochondrial membrane bound adaptor protein Miro1 or Miro2 (Debattisti et al, 2017;Li et al, 2021). When Miro1 is knocked out from many cell types this results in mitochondria becoming restricted around the nucleus compared to when Miro1 is present, and the mitochondria are strategically and dynamically re-localized throughout the cytoplasm (Ahmad et al, 2014;Schuler et al, 2017;Alshaabi et al, 2021) (Figure 3A).…”

Section: Mitochondrial Trafficking Dynamicsmentioning

confidence: 99%

Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes

Shannon

Gravelle

Cunniff

2022

Front. Mol. Biosci.

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Regulation of cell signaling cascades is critical in making sure the response is activated spatially and for a desired duration. Cell signaling cascades are spatially and temporally controlled through local protein phosphorylation events which are determined by the activation of specific kinases and/or inactivation of phosphatases to elicit a complete and thorough response. For example, A-kinase-anchoring proteins (AKAPs) contribute to the local regulated activity protein kinase A (PKA). The activity of kinases and phosphatases can also be regulated through redox-dependent cysteine modifications that mediate the activity of these proteins. A primary example of this is the activation of the epidermal growth factor receptor (EGFR) and the inactivation of the phosphatase and tensin homologue (PTEN) phosphatase by reactive oxygen species (ROS). Therefore, the local redox environment must play a critical role in the timing and magnitude of these events. Mitochondria are a primary source of ROS and energy (ATP) that contributes to redox-dependent signaling and ATP-dependent phosphorylation events, respectively. The strategic positioning of mitochondria within cells contributes to intracellular gradients of ROS and ATP, which have been shown to correlate with changes to protein redox and phosphorylation status driving downstream cellular processes. In this review, we will discuss the relationship between subcellular mitochondrial positioning and intracellular ROS and ATP gradients that support dynamic oxidation and phosphorylation signaling and resulting cellular effects, specifically associated with cell migration signaling.

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Section: Mitochondrial Trafficking Dynamicsmentioning

confidence: 99%

Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes

Shannon

Gravelle

Cunniff

2022

Front. Mol. Biosci.

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“…The failure to remove Miro1 from damaged mitochondria in fibroblasts of MAPT patients ( Figure 1 ) is reminiscent of that observed in fibroblasts of PD patients ( Hsieh et al, 2019 ). We have previously discovered a small molecule (named Miro1 Reducer or MR3) that binds to and destabilizes human Miro1 protein ( Hsieh et al, 2019 ; Li et al, 2021 ). Treating fibroblasts of PD patients with Miro1 Reducer rescues the phenotype of Miro1 accumulation on damaged mitochondria, and applying Miro1 Reducer to human neuron and fly models of PD ameliorates Parkinson’s relevant phenotypes, without affecting Miro1’s overall GTPase activity or other mitochondrial proteins including Miro2, Mitofusin, OPA1, VDAC, and ATP5β ( Hsieh et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients

Bharat

Hsieh

Wang

2021

Front. Cell Dev. Biol.

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Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients’ fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention.

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“…This stalling of mitochondrial fission results in dramatic changes to cristae morphology, notably a decrease in cristae score and number, indicative of immature and poorly formed cristae. Changes in redox signaling can lead to cysteine oxidation of MIC60 (Li et al, 2021; Wasilewski and Chacinska, 2021), an inner mitochondrial membrane protein responsible for cristae structure integrity. Thus, the lack of proper mitochondrial fission in patient cells may disrupt redox signaling, which may in turn be responsible for the aberrant cristae morphology detected in patient cells.…”

Section: Discussionmentioning

confidence: 99%

DRP1-mediated mitochondrial fission is essential to maintain cristae morphology and bioenergetics

Robertson

Riffle

Patel

et al. 2022

Preprint

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Mitochondria and peroxisomes are both dynamic signaling organelles that constantly undergo fission. While mitochondrial fission is known to coordinate cellular metabolism, proliferation, and apoptosis, the physiological relevance of peroxisome dynamics and the implications for cell fate are not fully understood. DRP1 (dynamin-related protein 1) is an essential GTPase that executes both mitochondrial and peroxisomal fission. Patients with de novo heterozygous missense mutations in the gene that encodes DRP1, DNM1L, present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1). EMPF1 is a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we utilized human-derived fibroblasts from patients with mutations in DRP1 who present with EMPF1. As expected, patient cells display elongated mitochondrial morphology and lack of fission. Patient cells display a lower coupling efficiency of the electron transport chain, increased proton leak, and upregulation of glycolysis. In addition to these metabolic abnormalities, mitochondrial hyperfusion results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential, both of which are tightly linked to the changes in metabolism. Peroxisome structure is also severely elongated in patient cells and results in a potential functional compensation of fatty acid oxidation. Understanding the mechanism by which DRP1 mutations cause these metabolic changes will give insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.

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A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation

Cited by 32 publications

References 67 publications

Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes

Mitochondrial trafficking and redox/phosphorylation signaling supporting cell migration phenotypes

Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients

DRP1-mediated mitochondrial fission is essential to maintain cristae morphology and bioenergetics

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