bims-mitdyn 2024-10-13 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2024–10–13
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine

Coordinating BNIP3/NIX-mediated mitophagy in space and time.
Ribosomes hibernate on mitochondria during cellular stress.
A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.
DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
Generation of transmitochondrial cybrids in cancer cells.
Mitochondrial RNA maturation.
Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Accelerated mitochondrial dynamics promote spermatogonial differentiation.
Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.
Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Biochem Soc Trans. 2024 Oct 08. pii: BST20221364. [Epub ahead of print]

Coordinating BNIP3/NIX-mediated mitophagy in space and time.

Natalie M Niemi, Jonathan R Friedman.

  Mitochondria maintain organellar homeostasis through multiple quality control pathways, including the clearance of defective or unwanted mitochondria by selective autophagy. This removal of mitochondria, mitophagy, is controlled in large part by the outer mitochondrial membrane mitophagy receptors BNIP3 and NIX. While it has long been appreciated that BNIP3 and NIX mediate mitophagy by controlling the recruitment of autophagic machinery to the mitochondrial surface, the requirement for the carefully controlled spatiotemporal regulation of receptor-mediated mitophagy has only recently come to light. Several new factors that regulate the BNIP3/NIX-mediated mitophagy pathway have emerged, and various loss-of-function cell and animal models have revealed the dire consequences of their dysregulation. In this mini-review, we discuss new insights into the mechanisms and roles of the regulation of BNIP3 and NIX and highlight questions that have emerged from the identification of these new regulators.

Keywords:  autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1042/BST20221364
Nat Commun. 2024 Oct 08. 15(1): 8666

Ribosomes hibernate on mitochondria during cellular stress.

Olivier Gemin, Maciej Gluc, Higor Rosa, Michael Purdy, Moritz Niemann, Yelena Peskova, Simone Mattei, Ahmad Jomaa.

Cell survival under nutrient-deprived conditions relies on cells' ability to adapt their organelles and rewire their metabolic pathways. In yeast, glucose depletion induces a stress response mediated by mitochondrial fragmentation and sequestration of cytosolic ribosomes on mitochondria. This cellular adaptation promotes survival under harsh environmental conditions; however, the underlying mechanism of this response remains unknown. Here, we demonstrate that upon glucose depletion protein synthesis is halted. Cryo-electron microscopy structure of the ribosomes show that they are devoid of both tRNA and mRNA, and a subset of the particles depicted a conformational change in rRNA H69 that could prevent tRNA binding. Our in situ structural analyses reveal that the hibernating ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface. Notably, we show that hibernating ribosomes exclusively bind to the outer mitochondrial membrane via the small ribosomal subunit during cellular stress. We identify the ribosomal protein Cpc2/RACK1 as the molecule mediating ribosomal tethering to mitochondria. This study unveils the molecular mechanism connecting mitochondrial stress with the shutdown of protein synthesis and broadens our understanding of cellular responses to nutrient scarcity and cell quiescence.

DOI: https://doi.org/10.1038/s41467-024-52911-4
Nat Commun. 2024 Oct 08. 15(1): 8723

A germline-to-soma signal triggers an age-related decline of mitochondrial stress response.

Liankui Zhou, Liu Jiang, Lan Li, Chengchuan Ma, Peixue Xia, Wanqiu Ding, Ying Liu.

The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRmt) upon mitochondrial perturbations. This discovery led to subsequent investigations that unveil a hedgehog-like signal that is transmitted from the germline to the soma in adults to inhibit UPRmt in somatic tissues. Additionally, we find that the levels of germline-expressed piRNAs in adult animals markedly decreased. This reduction in piRNA levels coincides with the production and secretion of a hedgehog-like signal and suppression of the UPRmt in somatic cells. Building upon existing research, our study further elucidates the intricate mechanisms of germline-to-soma signaling and its role in modulating the trade-offs between reproduction and somatic maintenance within the context of organismal aging.

DOI: https://doi.org/10.1038/s41467-024-53064-0
EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

  Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00242-x
Methods Cell Biol. 2024 ;pii: S0091-679X(24)00152-3. [Epub ahead of print]189 23-40

Generation of transmitochondrial cybrids in cancer cells.

Ruth Soler-Agesta, Cristina Ripollés-Yuba, Joaquín Marco-Brualla, Raquel Moreno-Loshuertos, Ai Sato, Manuel Beltrán-Visiedo, Lorenzo Galluzzi, Alberto Anel.

  At odds with historical views suggesting that mitochondrial functions are largely dispensable for cancer cells, it is now clear that mitochondria have a major impact on malignant transformation, tumor progression and response to treatment. Mitochondria are indeed critical for neoplastic cells not only as an abundant source of ATP and other metabolic intermediates, but also as gatekeepers of apoptotic cell death and inflammation. Interestingly, while mitochondrial components are mostly encoded by nuclear genes, mitochondria contain a small, circular genome that codes for a few mitochondrial proteins, ribosomal RNAs and transfer RNAs. Here, we describe a straightforward method to generate transmitochondrial cybrids, i.e., cancer cells depleted of their mitochondrial DNA and reconstituted with intact mitochondria from another cellular source. Once established, transmitochondrial cybrids can be stably propagated and are valuable to dissect the specific impact of the mitochondrial genome on cancer cell functions.

Keywords:  22Rv1 cells; Cancer metabolism; DU-145 cells; Immunity; mtDNA; rho(0) cells

DOI:  https://doi.org/10.1016/bs.mcb.2024.05.010
RNA Biol. 2024 Jan;21(1): 28-39

Mitochondrial RNA maturation.

Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.

  The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.

Keywords:  Mitochondrial; maturation; messenger RNA; modifications; processing; translation

DOI:  https://doi.org/10.1080/15476286.2024.2414157
Nat Commun. 2024 Oct 07. 15(1): 8682

Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.

Lucia Del Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime de Juan-Sanz, Alba Fernández-Rodrigo, José A Esteban, Mònica Girona, Albert Quintana, Eduardo Balsa.

Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management.

DOI: https://doi.org/10.1038/s41467-024-52968-1
Stem Cell Reports. 2024 Sep 28. pii: S2213-6711(24)00268-6. [Epub ahead of print]

Accelerated mitochondrial dynamics promote spermatogonial differentiation.

Zhaoran Zhang, Junru Miao, Hanben Wang, Izza Ali, Duong Nguyen, Wei Chen, Yuan Wang.

  At different stages of spermatogenesis, germ cell mitochondria differ remarkably in morphology, architecture, and functions. However, it remains elusive how mitochondria change their features during spermatogonial differentiation, which in turn impacts spermatogonial stem cell fate decision. In this study, we observed that mitochondrial fusion and fission were both upregulated during spermatogonial differentiation. As a result, the mitochondrial morphology remained unaltered. Enhanced mitochondrial fusion and fission promoted spermatogonial differentiation, while the deficiency in DRP1-mediated fission led to a stage-specific blockage of spermatogenesis at differentiating spermatogonia. Our data further revealed that increased expression of pro-fusion factor MFN1 upregulated mitochondrial metabolism, whereas DRP1 specifically regulated mitochondrial permeability transition pore opening in differentiating spermatogonia. Taken together, our findings unveil how proper spermatogonial differentiation is precisely controlled by concurrently accelerated and properly balanced mitochondrial fusion and fission in a germ cell stage-specific manner, thereby providing critical insights about mitochondrial contribution to stem cell fate decision.

Keywords:  DRP1; MFN1; mitochondrial dynamics; spermatogonial differentiation; spermatogonial stem cells

DOI:  https://doi.org/10.1016/j.stemcr.2024.09.006
Dev Cell. 2024 Oct 07. pii: S1534-5807(24)00532-X. [Epub ahead of print]59(19): 2549-2565

Dynamic death decisions: How mitochondrial dynamics shape cellular commitment to apoptosis and ferroptosis.

Jesminara Khatun, Jesse D Gelles, Jerry Edward Chipuk.

  The incorporation of mitochondria into early eukaryotes established organelle-based biochemistry and enabled metazoan development. Diverse mitochondrial biochemistry is essential for life, and its homeostatic control via mitochondrial dynamics supports organelle quality and function. Mitochondrial crosstalk with numerous regulated cell death (RCD) pathways controls the decision to die. In this review, we will focus on apoptosis and ferroptosis, two distinct forms of RCD that utilize divergent signaling to kill a targeted cell. We will highlight how proteins and processes involved in mitochondrial dynamics maintain biochemically diverse subcellular compartments to support apoptosis and ferroptosis machinery, as well as unite disparate RCD pathways through dual control of organelle biochemistry and the decision to die.

Keywords:  apoptosis; cell biology; cell death; ferroptosis; membranes; mitochondria; mitochondrial dynamics; signal transduction

DOI:  https://doi.org/10.1016/j.devcel.2024.09.004
Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2411672121

Nuclear compensatory evolution driven by mito-nuclear incompatibilities.

Debora Princepe, Marcus A M de Aguiar.

  Mitochondrial function relies on the coordinated expression of mitochondrial and nuclear genes, exhibiting remarkable resilience despite high mitochondrial mutation rates. The nuclear compensation mechanism suggests deleterious mitochondrial alleles drive compensatory nuclear mutations to preserve mito-nuclear compatibility. However, prevalence and factors conditioning this phenomenon remain debated due to its conflicting evidence. Here, we investigate how mito-nuclear incompatibilities impact substitutions in a model for species radiation. Mating success depends on genetic compatibility (nuclear DNA) and spatial proximity. Populations evolve from partially compatible mito-nuclear states, simulating mitochondrial DNA (mtDNA) introgression. Mutations do not confer advantages nor disadvantages, but individual fecundity declines with increasing incompatibilities, selecting for mito-nuclear coordination. We find that selection for mito-nuclear compatibility affects each genome differently based on their initial state. In compatible gene pairs, selection reduces substitutions in both genomes, while in incompatible nuclear genes, it consistently promotes compensation, facilitated by more mismatches. Interestingly, high mitochondrial mutation rates can reduce nuclear compensation by increasing mtDNA rectification, while substitutions in initially compatible nuclear gene are boosted. Finally, the presence of incompatibilities accelerates species radiation, but equilibrium richness is not directly correlated to substitution rates, revealing the complex dynamics triggered by mitochondrial introgression and mito-nuclear coevolution. Our study provides a perspective on nuclear compensation and the role of mito-nuclear incompatibilities in speciation by exploring extreme scenarios and identifying trends that empirical data alone cannot reveal. We emphasize the challenges in detecting these dynamics and propose analyzing specific genomic signatures could shed light on this evolutionary process.

Keywords:  mito-nuclear coevolution; mitochondrial mutation rate; mtDNA introgression; nuclear compensation

DOI:  https://doi.org/10.1073/pnas.2411672121