bims-mitdyn 2022-03-06 papers

Issue of 2022‒03‒06
seven papers selected by
Edmond Chan
Queen’s University, School of Medicine

Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00108-3. [Epub ahead of print]82(5): 1066-1077.e7

MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.

Sotirios D Zervopoulos, Aristeidis E Boukouris, Bruno Saleme, Alois Haromy, Saymon Tejay, Gopinath Sutendra, Evangelos D Michelakis.

The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points. A decrease in nuclear MFN2 levels decreases mitochondria tethering and nPDC levels. Mitochondrial PDC crosses the NE and interacts with lamin A, forming a ring below the NE before crossing through the lamin layer into the nucleoplasm, in areas away from NPCs. Effective blockage of NPC trafficking does not decrease nPDC levels. The PDC-lamin interaction is maintained during cell division, when lamin depolymerizes and disassembles before reforming daughter nuclear envelopes, providing another pathway for nPDC entry during mitosis. Our work provides a different angle to understanding mitochondria-to-nucleus communication and nuclear metabolism.

Keywords: acetylation; cell cycle; lamin; metabolism; mitochondria; mitofusin; nucleus; protein trafficking; pyruvate dehydrogenase complex; tethering

DOI: https://doi.org/10.1016/j.molcel.2022.02.003

Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00119-8. [Epub ahead of print]82(5): 886-888

Bypassing the nuclear gate: A non-canonical entry pathway for the mitochondrial pyruvate dehydrogenase complex.

Emily Boyle, Florian Wilfling.

Zervopoulos et al. (2022) propose a non-canonical nuclear import pathway for the functional mitochondrial pyruvate dehydrogenase complex (PDC), facilitated by dynamic MFN2-mediated tethering of mitochondria to the nuclear envelope upon exposure to proliferative stimuli.

DOI: https://doi.org/10.1016/j.molcel.2022.02.014

Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00171-1. [Epub ahead of print]38(9): 110444

Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.

Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.

Keywords: C. elegans; MondoA; Rubicon; aging; autophagy; cellular senescence; kidney; mitochondrial homeostasis; mml-1; peroxiredoxin 3

DOI: https://doi.org/10.1016/j.celrep.2022.110444

Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11

Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.

Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

Keywords: S. cerevisiae; cell biology

DOI: https://doi.org/10.7554/eLife.75658

Brain. 2022 Mar 04. pii: awab303. [Epub ahead of print]

CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.

Anastasia Rumyantseva, Milica Popovic, Aleksandra Trifunovic.

Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. Therefore, it is not surprising that mutations in either mtDNA or nuclear DNA-encoded genes of mitochondrial proteins cause diseases affecting the oxidative phosphorylation system, which are heterogeneous from a clinical, genetic, biochemical and molecular perspective and can affect patients at any age. Despite all this, it is surprising that our understanding of the mechanisms governing mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored. We recently showed that loss of the mitochondrial matrix protease caseinolytic protease proteolytic subunit (CLPP) ameliorates phenotypes in cells characterized by defects in oxidative phosphorylation maintenance. Here, we build upon this finding by showing that CLPP depletion is indeed beneficial in vivo for various types of neuronal populations, including Purkinje cells in the cerebellum and cortical and hippocampal neurons in the forebrain, as it strongly improves distinct phenotypes of mitochondria encephalopathy, driven by the deficiency of the mitochondrial aspartyl tRNA synthase DARS2. In the absence of CLPP, neurodegeneration of DARS2-deficient neurons is delayed as they present milder oxidative phosphorylation dysfunction. This in turn leads to a decreased neuroinflammatory response and significantly improved motor functions in both double-deficient models (Purkinje cell-specific or forebrain neuron-specific Dars2/Clpp double knockout mice). We propose that diminished turnover of respiratory complex I caused by the loss of CLPP is behind the improved phenotype in Dars2/Clpp double knockout animals, even though this intervention might not restore respiratory complex I activity but rather improve mitochondrial cristae morphology or help maintain the NAD+/NADH ratio inside mitochondria. These results also open the possibility of targeting CLPP activity in many other mitochondrial encephalopathies characterized by respiratory complex I instability.

Keywords: CLPP protease; DARS2 deficiency; LBSL; mitochondrial diseases

DOI: https://doi.org/10.1093/brain/awab303

PLoS Biol. 2022 Mar;20(3): e3001380

The ER membrane complex (EMC) can functionally replace the Oxa1 insertase in mitochondria.

Büsra Güngör, Tamara Flohr, Sriram G Garg, Johannes M Herrmann.

Two multisubunit protein complexes for membrane protein insertion were recently identified in the endoplasmic reticulum (ER): the guided entry of tail anchor proteins (GET) complex and ER membrane complex (EMC). The structures of both of their hydrophobic core subunits, which are required for the insertion reaction, revealed an overall similarity to the YidC/Oxa1/Alb3 family members found in bacteria, mitochondria, and chloroplasts. This suggests that these membrane insertion machineries all share a common ancestry. To test whether these ER proteins can functionally replace Oxa1 in yeast mitochondria, we generated strains that express mitochondria-targeted Get2-Get1 and Emc6-Emc3 fusion proteins in Oxa1 deletion mutants. Interestingly, the Emc6-Emc3 fusion was able to complement an Δoxa1 mutant and restored its respiratory competence. The Emc6-Emc3 fusion promoted the insertion of the mitochondrially encoded protein Cox2, as well as of nuclear encoded inner membrane proteins, although was not able to facilitate the assembly of the Atp9 ring. Our observations indicate that protein insertion into the ER is functionally conserved to the insertion mechanism in bacteria and mitochondria and adheres to similar topological principles.

DOI: https://doi.org/10.1371/journal.pbio.3001380

Trends Cell Biol. 2022 Feb 24. pii: S0962-8924(22)00034-4. [Epub ahead of print]

Long-lived mitochondrial proteins and why they exist.

Ewa Bomba-Warczak, Jeffrey N Savas.

Intracellular long-lived proteins (LLPs) provide structural support for several highly stable protein complexes and assemblies that play essential roles in ensuring cellular homeostasis and function. Recently, mitochondrial long-lived proteins (mt-LLPs) were discovered within inner mitochondria membranes (IMMs) and cristae invagination in tissues with old postmitotic cells. This observation is at odds with the fact that mitochondria are highly dynamic organelles that are continually remodeled through processes of fission, fusion, biogenesis, and multiple quality control pathways. In this opinion article, we propose that a subset of the mitochondrial proteome persists over long time frames and these mt-LLPs provide key structural support for the lifelong maintenance of mitochondrial structure.

Keywords: cristae ultrastructure; long-lived proteins; mitochondria; mitochondrial dynamics; protein turnover; stable structures

DOI: https://doi.org/10.1016/j.tcb.2022.02.001