Introducing JCS snapshots

At The Company of Biologists, we’re always looking for new ways to help authors promote their research. We have therefore introduced ‘JCS snapshots’ where we invite the authors of recently published articles to produce short videos to present the main findings in their research. Below, you can browse through ‘JCS snapshots’ from the Tavernarakis lab, Ghosh & Sengupta labs, Birgisdottir lab and Mears lab. This research was published in our recent ‘Cell biology of mitochondria’ special issue.

Fis1 regulates mitochondrial morphology, bioenergetics and removal of mitochondrial DNA damage in irradiated glioblastoma cells
Yuli Buckley, Maria S. K. Stoll, Charles L. Hoppel, Jason A. Mears

Speaker: Yuli Buckley

In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress, and we uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered electron transport chain (ETC) activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.

Mitophagy is induced in human engineered heart tissue after simulated ischemia and reperfusion
Mireia Nàger, Kenneth B. Larsen, Zambarlal Bhujabal, Trine B. Kalstad, Judith Rössinger, Truls Myrmel, Florian Weinberger, Asa B. Birgisdottir

Speaker: Mireia Nàger

The paradoxical exacerbation of cellular injury and death during reperfusion remains a problem in the treatment of myocardial infarction. Mitochondrial dysfunction plays a key role in the pathogenesis of myocardial ischemia and reperfusion injury. Dysfunctional mitochondria can be removed by mitophagy, culminating in their degradation within acidic lysosomes. Mitophagy is pivotal in maintaining cardiac homeostasis and emerges as a potential therapeutic target. Here, we employed beating human engineered heart tissue (EHT) to assess mitochondrial dysfunction and mitophagy during ischemia and reperfusion simulation. Our data indicate adverse ultrastructural changes in mitochondrial morphology and impairment of mitochondrial respiration. Furthermore, our pH-sensitive mitophagy reporter EHTs, generated by a CRISPR/Cas9 endogenous knock-in strategy, revealed induced mitophagy flux in EHTs after ischemia and reperfusion simulation. The induced flux required the activity of the protein kinase ULK1, a member of the core autophagy machinery. Our results demonstrate the applicability of the reporter EHTs for mitophagy assessment in a clinically relevant setting. Deciphering mitophagy in the human heart will facilitate development of novel therapeutic strategies.

NHR-85 modulates mitochondrial and lipid homeostasis to protect against α-synuclein aggregation in C. elegans
Dikaia Tsagkari, Maria Markaki, Nektarios Tavernarakis

Speaker: Dikaia Tsagkari

Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson’s disease, suggesting that it might play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.

Pyruvate plus uridine augments mitochondrial respiration and prevents cardiac hypertrophy in zebrafish and H9c2 cells
Soumyajit Mukherjee, Shreya Das, Surajit Das, Samudra Gupta, Subhra Prakash Hui, Arunima Sengupta, Alok Ghosh

Speaker: Alok Ghosh

Dysfunction of mitochondrial pyruvate oxidation and aberrant respiratory chain components are common in cardiac defects. However, the precise role of mitochondrial respiration in cardiomyocyte hypertrophy is unclear. Phenylephrine (PE) treatment of rat neonatal H9c2 cardiomyocytes promotes significant hypertrophy with decreased mitochondrial oxygen consumption rate (OCR), membrane potential, respiratory subunit NDUFB8, UQCRC2 and ATP5A (ATP5F1A) expression, and accumulation of reactive oxygen species (ROS). Surprisingly, a 60% reduction in cell survival was observed in PE-treated cells relative to control cells when grown under the respiratory-proficient galactose medium. To revert H9c2 hypertrophy and increase survival, we performed a screening with compounds that boost mitochondrial OCR and scavenge ROS, and identified pyruvate plus uridine as the best hit. As corroboration of the in vitro study, supplementation of pyruvate plus uridine significantly prevented PE-induced cardiac hypertrophy, pericardial edema and bradycardia symptoms in zebrafish embryos. Moreover, pyruvate plus uridine decreased the ventricular and atrial area in cardiomyocyte-specific GFP transgenic Tg (myl7:HRAS-EGFP) lines. Using in vitro and in vivo models, we show that boosting of mitochondrial respiration through pyruvate supplementation and scavenging ROS through uridine supplementation jointly ameliorate cardiac hypertrophy and bradycardia symptoms.

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