bims-agreso 2023-10-15 papers

Issue of 2023–10–15
five papers selected by
Joel Christie, Tata Memorial Centre

Mol Cell. 2023 Oct 08. pii: S1097-2765(23)00753-0. [Epub ahead of print]

Mitochondrial DNA breaks activate an integrated stress response to reestablish homeostasis.

Yi Fu, Olivia Sacco, Emily DeBitetto, Evgeny Kanshin, Beatrix Ueberheide, Agnel Sfeir.

Mitochondrial DNA double-strand breaks (mtDSBs) lead to the degradation of circular genomes and a reduction in copy number; yet, the cellular response in human cells remains elusive. Here, using mitochondrial-targeted restriction enzymes, we show that a subset of cells with mtDSBs exhibited defective mitochondrial protein import, reduced respiratory complexes, and loss of membrane potential. Electron microscopy confirmed the altered mitochondrial membrane and cristae ultrastructure. Intriguingly, mtDSBs triggered the integrated stress response (ISR) via the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) by DELE1 and heme-regulated eIF2α kinase (HRI). When ISR was inhibited, the cells experienced intensified mitochondrial defects and slower mtDNA recovery post-breakage. Lastly, through proteomics, we identified ATAD3A-a membrane-bound protein interacting with nucleoids-as potentially pivotal in relaying signals from impaired genomes to the inner mitochondrial membrane. In summary, our study delineates the cascade connecting damaged mitochondrial genomes to the cytoplasm and highlights the significance of the ISR in maintaining mitochondrial homeostasis amid genome instability.

Keywords: ATAD3A; double-strand breaks; integrated stress response; mitochondrial DNA; protein import

DOI: https://doi.org/10.1016/j.molcel.2023.09.026

Int J Mol Sci. 2023 Sep 22. pii: 14421. [Epub ahead of print]24(19):

Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.

Hariprasath Ragupathy, Manasvi Vukku, Sandeep Kumar Barodia.

Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergo phenotypic alterations that can lead to neuroinflammation, which is a well-accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of the neuronal population due to increased oxidative stress leads to neurodegenerative diseases, mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is a key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitute a significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decide the fate of overall brain health; therefore, it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable the diversity and highly synchronized connecting property of non-neuronal cells are in keeping the neurons healthy to control neurodegeneration.

Keywords: astrocytes; microglia; mitochondria; neurons; oligodendrocytes; oxidative stress

DOI: https://doi.org/10.3390/ijms241914421

Nat Rev Immunol. 2023 Oct 13.

The cancer-immune dialogue in the context of stress.

Yuting Ma, Guido Kroemer.

Although there is little direct evidence supporting that stress affects cancer incidence, it does influence the evolution, dissemination and therapeutic outcomes of neoplasia, as shown in human epidemiological analyses and mouse models. The experience of and response to physiological and psychological stressors can trigger neurological and endocrine alterations, which subsequently influence malignant (stem) cells, stromal cells and immune cells in the tumour microenvironment, as well as systemic factors in the tumour macroenvironment. Importantly, stress-induced neuroendocrine changes that can regulate immune responses have been gradually uncovered. Numerous stress-associated immunomodulatory molecules (SAIMs) can reshape natural or therapy-induced antitumour responses by engaging their corresponding receptors on immune cells. Moreover, stress can cause systemic or local metabolic reprogramming and change the composition of the gastrointestinal microbiota which can indirectly modulate antitumour immunity. Here, we explore the complex circuitries that link stress to perturbations in the cancer-immune dialogue and their implications for therapeutic approaches to cancer.

DOI: https://doi.org/10.1038/s41577-023-00949-8

Nat Commun. 2023 Oct 10. 14(1): 6328

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-42093-w

PLoS Comput Biol. 2023 Oct 13. 19(10): e1011554

Short-term neuronal and synaptic plasticity act in synergy for deviance detection in spiking networks.

Felix Benjamin Kern, Zenas C Chao.

Sensory areas of cortex respond more strongly to infrequent stimuli when these violate previously established regularities, a phenomenon known as deviance detection (DD). Previous modeling work has mainly attempted to explain DD on the basis of synaptic plasticity. However, a large fraction of cortical neurons also exhibit firing rate adaptation, an underexplored potential mechanism. Here, we investigate DD in a spiking neuronal network model with two types of short-term plasticity, fast synaptic short-term depression (STD) and slower threshold adaptation (TA). We probe the model with an oddball stimulation paradigm and assess DD by evaluating the network responses. We find that TA is sufficient to elicit DD. It achieves this by habituating neurons near the stimulation site that respond earliest to the frequently presented standard stimulus (local fatigue), which diminishes the response and promotes the recovery (global fatigue) of the wider network. Further, we find a synergy effect between STD and TA, where they interact with each other to achieve greater DD than the sum of their individual effects. We show that this synergy is caused by the local fatigue added by STD, which inhibits the global response to the frequently presented stimulus, allowing greater recovery of TA-mediated global fatigue and making the network more responsive to the deviant stimulus. Finally, we show that the magnitude of DD strongly depends on the timescale of stimulation. We conclude that highly predictable information can be encoded in strong local fatigue, which allows greater global recovery and subsequent heightened sensitivity for DD.

DOI: https://doi.org/10.1371/journal.pcbi.1011554