bims-mikwok 2021-09-12 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2021–09–12
seven papers selected by
Avinash N. Mukkala, University of Toronto

The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.
Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.
ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.
Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.
Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
The Mitochondrial Ca2+ Uniporter is a Central Regulator of Interorganellar Ca2+ Transfer and NFAT Activation.
Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.

Autophagy. 2021 Sep 05. 1-3

The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.

Yumiko Oshima, Nicolas Verhoeven, Etienne Cartier, Mariusz Karbowski.

  Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Formation of mosaic mitochondria requires mitochondrial fission and active mitochondrial translation. In cell lines deficient in PRKN activity, this process is followed by severing the outer mitochondrial membrane (OMM) and ubiquitination of the inner mitochondrial membrane (IMM) proteins (including TRAP1 and CPOX), recruitment of autophagy receptors, and formation of mito-autophagosomes. In contrast, in PRKN-expressing cells, mitochondria with high CYCS and CPOX levels are preferentially targeted by PRKN, leading to OMM ubiquitination and canonical PRKN-PINK1-mediated autophagy.

Keywords:  DRP1; Parkin; mitochondria; mitochondrial translation; mitophagy; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2021.1964887
Proc Natl Acad Sci U S A. 2021 Sep 14. pii: e2025932118. [Epub ahead of print]118(37):

Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy.

Joshua C Drake, Rebecca J Wilson, Rhianna C Laker, Yuntian Guan, Hannah R Spaulding, Anna S Nichenko, Wenqing Shen, Huayu Shang, Maya V Dorn, Kian Huang, Mei Zhang, Aloka B Bandara, Matthew H Brisendine, Jennifer A Kashatus, Poonam R Sharma, Alexander Young, Jitendra Gautam, Ruofan Cao, Horst Wallrabe, Paul A Chang, Michael Wong, Eric M Desjardins, Simon A Hawley, George J Christ, David F Kashatus, Clint L Miller, Matthew J Wolf, Ammasi Periasamy, Gregory R Steinberg, D Grahame Hardie, Zhen Yan.

  Mitochondria form a complex, interconnected reticulum that is maintained through coordination among biogenesis, dynamic fission, and fusion and mitophagy, which are initiated in response to various cues to maintain energetic homeostasis. These cellular events, which make up mitochondrial quality control, act with remarkable spatial precision, but what governs such spatial specificity is poorly understood. Herein, we demonstrate that specific isoforms of the cellular bioenergetic sensor, 5' AMP-activated protein kinase (AMPKα1/α2/β2/γ1), are localized on the outer mitochondrial membrane, referred to as mitoAMPK, in various tissues in mice and humans. Activation of mitoAMPK varies across the reticulum in response to energetic stress, and inhibition of mitoAMPK activity attenuates exercise-induced mitophagy in skeletal muscle in vivo. Discovery of a mitochondrial pool of AMPK and its local importance for mitochondrial quality control underscores the complexity of sensing cellular energetics in vivo that has implications for targeting mitochondrial energetics for disease treatment.

Keywords:  AMPK; exercise; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2025932118
Nat Commun. 2021 Sep 09. 12(1): 5354

ORP1L mediated PI(4)P signaling at ER-lysosome-mitochondrion three-way contact contributes to mitochondrial division.

Maxime Boutry, Peter K Kim.

Mitochondrial division is not an autonomous event but involves multiple organelles, including the endoplasmic reticulum (ER) and lysosomes. Whereas the ER drives the constriction of mitochondrial membranes, the role of lysosomes in mitochondrial division is not known. Here, using super-resolution live-cell imaging, we investigate the recruitment of lysosomes to the site of mitochondrial division. We find that the ER recruits lysosomes to the site of division through the interaction of VAMP-associated proteins (VAPs) with the lysosomal lipid transfer protein ORP1L to induce a three-way contact between the ER, lysosome, and the mitochondrion. We also show that ORP1L might transport phosphatidylinositol-4-phosphate (PI(4)P) from lysosomes to mitochondria, as inhibiting its transfer or depleting PI(4)P at the mitochondrial division site impairs fission, demonstrating a direct role for PI(4)P in the division process. Our findings support a model where the ER recruits lysosomes to act in concert at the fission site for the efficient division of mitochondria.

DOI: https://doi.org/10.1038/s41467-021-25621-4
BMB Rep. 2021 Sep 07. pii: 5388. [Epub ahead of print]

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

Shin-Hye Yu, Soomin Kim, Yujin Kim, Seo-Eun Lee, Jong Hyeok Park, Gayoung Cho, Jong-Cheon Ha, Hahnsun Jung, Sang-Min Lim, Kyuboem Han, Hong Kyu Lee, Young Cheol Kang, Chun-Hyung Kim.

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could significantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses.
Blood Adv. 2021 Sep 10. pii: bloodadvances.2020003661. [Epub ahead of print]

Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.

Kaori Saito, Qi Zhang, Haeun Yang, Kotoko Yamatani, Tomohiko Ai, Vivian Ruvolo, Natalia Baran, Tianyu Cai, Helen Ma, Rodrigo Jacamo, Vinitha Mary Kuruvilla, Junichi Imoto, Sonoko Kinjo, Kazuho Ikeo, Kaori Moriya, Koya Suzuki, Takashi Miida, Yong-Mi Kim, Christopher P Vellano, Michael Andreeff, Joseph R Marszalek, Yoko Tabe, Marina Y Konopleva.

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.

DOI: https://doi.org/10.1182/bloodadvances.2020003661
J Biol Chem. 2021 Sep 06. pii: S0021-9258(21)00976-5. [Epub ahead of print] 101174

The Mitochondrial Ca2+ Uniporter is a Central Regulator of Interorganellar Ca2+ Transfer and NFAT Activation.

Ryan E Yoast, Scott M Emrich, Xuexin Zhang, Ping Xin, Vikas Arige, Trayambak Pathak, J Cory Benson, Martin T Johnson, Ahmed Emam Abdelnaby, Natalia Lakomski, Nadine Hempel, Jung Min Han, Geneviève Dupont, David I Yule, James Sneyd, Mohamed Trebak.

  Mitochondrial Ca2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C-coupled receptors to that of cellular bioenergetics. However, how Ca2+ uptake by the mitochondrial Ca2+ uniporter (MCU) shapes receptor-evoked inter-organellar Ca2+ signaling is unknown. Here, we used CRISPR/Cas9 gene knockout, sub-cellular Ca2+ imaging and mathematical modeling to show that MCU is a universal regulator of intracellular Ca2+ signaling across mammalian cell types. MCU activity sustains cytosolic Ca2+ signaling by preventing Ca2+-dependent inactivation (CDI) of store-operated Ca2+ release-activated Ca2+ (CRAC) channels and by inhibiting Ca2+ extrusion. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca2+ responses to store depletion. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca2+ oscillations, endoplasmic reticulum (ER) Ca2+ refilling, nuclear translocation of nuclear factor for activated T-cells (NFAT) transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Our data show that MCU has dual counterbalancing functions at the cytosol-mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca2+ clearance and buffering capacity of mitochondria reciprocally regulate inter-organellar Ca2+ transfer and NFAT nuclear translocation during receptor-evoked signaling. These findings highlight the critical dual function of the MCU not only in the acute Ca2+ buffering by mitochondria but also in shaping ER and cytosolic Ca2+ signals that regulate cellular transcription and function.

Keywords:  CRAC channels; MCU; NFAT; SOCE; calcium oscillations; calcium signaling; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2021.101174
Nat Commun. 2021 09 06. 12(1): 5270

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.

Miao Cui, Ayhan Atmanli, Maria Gabriela Morales, Wei Tan, Kenian Chen, Xue Xiao, Lin Xu, Ning Liu, Rhonda Bassel-Duby, Eric N Olson.

Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.

DOI: https://doi.org/10.1038/s41467-021-25653-w