bims-nenemi 2022-11-06 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2022–11–06
ten papers selected by
Marco Tigano, Thomas Jefferson University

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.
Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.
ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.
Macrophage-mediated immune response aggravates hearing disfunction caused by the disorder of mitochondrial dynamics in cochlear hair cells.
Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.
Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis.
MARCH5 regulates mitotic apoptosis through MCL1-dependent and independent mechanisms.
Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.

J Cell Biol. 2023 Jan 02. pii: e202205045. [Epub ahead of print]222(1):

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.

Terytty Yang Li, Arwen W Gao, Xiaoxu Li, Hao Li, Yasmine J Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx.

To adapt mitochondrial function to the ever-changing intra- and extracellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1 and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.

DOI: https://doi.org/10.1083/jcb.202205045
Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00456-9. [Epub ahead of print]34(11): 1809-1823.e6

Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.

Jonathan M Palozzi, Swathi P Jeedigunta, Anastasia V Minenkova, Vernon L Monteiro, Zoe S Thompson, Toby Lieber, Thomas R Hurd.

  Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a conserved quality control mechanism that remains poorly understood. Here, through a large-scale screen, we uncover a unique programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We find that PGM is developmentally triggered as germ cells enter meiosis by inhibition of the target of rapamycin complex 1 (TORC1). We identify a role for the RNA-binding protein Ataxin-2 (Atx2) in coordinating the timing of PGM with meiosis. We show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission and translation factors, and members of the Atg1 complex, but not the mitophagy factors PINK1 and Parkin. Additionally, we report several factors that are critical for germline mtDNA quality control and show that pharmacological manipulation of one of these factors promotes mtDNA quality control.

Keywords:  autophagy; germ line; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection; quality control

DOI:  https://doi.org/10.1016/j.cmet.2022.10.005
Dev Cell. 2022 Oct 25. pii: S1534-5807(22)00720-1. [Epub ahead of print]

Two sensory neurons coordinate the systemic mitochondrial stress response via GPCR signaling in C. elegans.

Yangli Liu, Jun Zhou, Ning Zhang, Xueying Wu, Qian Zhang, Wenfeng Zhang, Xinyu Li, Ye Tian.

  Mitochondrial perturbations within neurons communicate stress signals to peripheral tissues, coordinating organismal-wide mitochondrial homeostasis for optimal fitness. However, the neuronal control of the systemic stress regulation remains poorly understood. Here, we identified a G-protein-coupled receptor (GPCR), SRZ-75, that couples with Gαq signaling in a pair of chemosensory ADL neurons to drive the mitochondrial unfolded protein response (UPRmt) activation in the intestine via the release of neuropeptides in Caenorhabditis elegans. Constitutive activation of Gαq signaling in the ADL neurons is sufficient to induce the intestinal UPRmt, leading to increased stress resistance and metabolic adaptations. Ablation of ADL neurons attenuates the intestinal UPRmt activation in response to various forms of neuronal mitochondrial dysfunction. Thus, GPCR and its Gαq downstream signaling in two sensory neurons coordinate the systemic UPRmt activation, representing a previously uncharacterized, but potentially conserved, neuronal signaling for organismal-wide mitochondrial stress regulation.

Keywords:  ADL chemosensory neurons; G-protein-coupled receptor; GPCR; Gαq signaling; SRZ-75; UPR(mt); cell-non-autonomous regulation; the mitochondrial unfolded protein response

DOI:  https://doi.org/10.1016/j.devcel.2022.10.001
EMBO J. 2022 Oct 31. e111550

Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.

Ying Shu, Yijie Hao, Junru Feng, Haiying Liu, Shi-Ting Li, Jiaqian Feng, Zetan Jiang, Ling Ye, Yingli Zhou, Yuchen Sun, Zilong Zhou, Haoran Wei, Ping Gao, Huafeng Zhang, Linchong Sun.

  Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.

Keywords:  ANT2; PHGDH; liver cancer; mitochondrial translation; mtEFG2

DOI:  https://doi.org/10.15252/embj.2022111550
Mol Metab. 2022 Nov 01. pii: S2212-8778(22)00192-2. [Epub ahead of print] 101623

ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.

Mikhaela B Slavin, Rita Kumari, David A Hood.

   OBJECTIVES: The Mitochondrial Unfolded Protein Response (UPRmt) is a compartment-specific mitochondrial quality control (MQC) mechanism that uses the transcription factor ATF5 to induce the expression of protective enzymes to restore mitochondrial function. Acute exercise is a stressor that has the potential to temporarily disrupt organellar protein homeostasis, however, the roles of ATF5 and the UPRmt in maintaining basal mitochondrial content, function and exercise-induced MQC mechanisms in skeletal muscle are not known.
METHODS: ATF5 KO and WT mice were examined at rest or after a bout of acute endurance exercise. We measured protein content in whole muscle, nuclear, cytosolic and mitochondrial fractions, in addition to mRNA transcript levels in whole muscle. Using isolated mitochondria, we quantified rates of oxygen consumption and ROS emission to observe the effects of the absence of ATF5 on organelle function.
RESULTS: ATF5 KO mice exhibited a larger and less functional muscle mitochondrial pool, most likely a culmination of enhanced biogenesis via increased PGC-1 α expression, and attenuated mitophagy. The absence of ATF5 resulted in a reduction in antioxidant proteins and increases in mitochondrial ROS emission, cytosolic cytochrome c, and the expression of mitochondrial chaperones. KO muscle also displayed enhanced exercise-induced stress kinase signaling, but a blunted mitophagic and UPRmt gene expression response, complemented by significant increases in the basal mRNA abundance and nuclear localization of ATF4. Instead of promoting its nuclear translocation, acute exercise caused the enrichment of ATF5 in mitochondrial fractions. We also identified PGC-1 α as an additional regulator of the basal expression of UPRmt genes.
CONCLUSION: The transcription factor ATF5 retains a critical role in the maintenance of mitochondrial homeostasis and the appropriate response of muscle to acute exercise for the optimization of mitochondrial quality control.

Keywords:  Exercise; Mitochondria; Mitochondrial Quality Control; Mitochondrial Unfolded Protein Response (UPR(mt)); Protein Homeostasis; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.molmet.2022.101623
Hum Mol Genet. 2022 Nov 04. pii: ddac270. [Epub ahead of print]

Macrophage-mediated immune response aggravates hearing disfunction caused by the disorder of mitochondrial dynamics in cochlear hair cells.

Yuan Zhang, Xiaolong Fu, Yiyuan Li, Wen Li, Guodong Hong, Siwei Guo, Yu Xiao, Ziyi Liu, Shuqin Ding, Xiuli Bi, Fanglei Ye, Jin Jin, Renjie Chai.

Mitochondrial dynamics is essential for maintaining the physiological function of the mitochondrial network, and the disorders of it leads to a variety of diseases. Our previous study identified mitochondrial dynamics controlled anti-tumor immune responses and anxiety symptoms. However, how mitochondrial dynamics affects auditory function in the inner ear remains unclear. Here, we show that deficiency of FAM73a or FAM73b, two mitochondrial outer membrane proteins that mediate mitochondrial fusion, lead to outer hair cells damage and progressive hearing loss in FVB/N mice. Abnormal mitochondrial fusion causes elevated oxidative stress and apoptosis of hair cells in early stage. Thereafter, the activation of macrophages and CD4+ T cell is found in the mutant mice with the increased expression of the inflammatory cytokines IL-12 and IFN-γ compared to control mice. Strikingly, dramatically decreased number of macrophages by LCCA treatment alleviates the hearing loss of mutant mice. Collectively, our finding highlights that FAM73a or FAM73b deficiency affects hair cells survival by disturbing mitochondrial function, and the subsequent immune response in the cochleae worsens the damage of hair cells.

DOI: https://doi.org/10.1093/hmg/ddac270
J Biol Chem. 2022 Oct 26. pii: S0021-9258(22)01081-X. [Epub ahead of print] 102638

Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.

Siddharth Sunilkumar, Allyson L Toro, Christopher F McCurry, Ashley M VanCleave, Shaunaci A Stevens, William P Miller, Scot R Kimball, Michael D Dennis.

  Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In wild-type cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (I-κB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of I-κB by enhancing both K63-ubiquitination and auto-phosphorylation of I-κB kinase (IKK) complex. In contrast with STZ-diabetic REDD1+/+ mice, IKK complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.

Keywords:  DDIT4 (REDD1); Diabetes; NF‐kappa B (NF‐KB); inflammation; retina

DOI:  https://doi.org/10.1016/j.jbc.2022.102638
Sci Signal. 2022 Nov;15(758): eabn8017

Doxorubicin causes ferroptosis and cardiotoxicity by intercalating into mitochondrial DNA and disrupting Alas1-dependent heme synthesis.

Ko Abe, Masataka Ikeda, Tomomi Ide, Tomonori Tadokoro, Hiroko Deguchi Miyamoto, Shun Furusawa, Yoshitomo Tsutsui, Ryo Miyake, Kosei Ishimaru, Masatsugu Watanabe, Shouji Matsushima, Tomoko Koumura, Ken-Ichi Yamada, Hirotaka Imai, Hiroyuki Tsutsui.

Clinical use of doxorubicin (DOX) is limited because of its cardiotoxicity, referred to as DOX-induced cardiomyopathy (DIC). Mitochondria-dependent ferroptosis, which is triggered by iron overload and excessive lipid peroxidation, plays a pivotal role in the progression of DIC. Here, we showed that DOX accumulated in mitochondria by intercalating into mitochondrial DNA (mtDNA), inducing ferroptosis in an mtDNA content-dependent manner. In addition, DOX disrupted heme synthesis by decreasing the abundance of 5'-aminolevulinate synthase 1 (Alas1), the rate-limiting enzyme in this process, thereby impairing iron utilization, resulting in iron overload and ferroptosis in mitochondria in cultured cardiomyocytes. Alas1 overexpression prevented this outcome. Administration of 5-aminolevulinic acid (5-ALA), the product of Alas1, to cultured cardiomyocytes and mice suppressed iron overload and lipid peroxidation, thereby preventing DOX-induced ferroptosis and DIC. Our findings reveal that the accumulation of DOX and iron in mitochondria cooperatively induces ferroptosis in cardiomyocytes and suggest that 5-ALA can be used as a potential therapeutic agent for DIC.

DOI: https://doi.org/10.1126/scisignal.abn8017
Cell Death Differ. 2022 Nov 03.

MARCH5 regulates mitotic apoptosis through MCL1-dependent and independent mechanisms.

Yang Wang, Randy Y C Poon.

The anti-apoptotic MCL1 is critical for delaying apoptosis during mitotic arrest. MCL1 is degraded progressively during mitotic arrest, removing its anti-apoptotic function. We found that knockout of components of ubiquitin ligases including APC/C, SCF complexes, and the mitochondrial ubiquitin ligase MARCH5 did not prevent mitotic degradation of MCL1. Nevertheless, MARCH5 determined the initial level of MCL1-NOXA network upon mitotic entry and hence the window of time during MCL1 was present during mitotic arrest. Paradoxically, although knockout of MARCH5 elevated mitotic MCL1, mitotic apoptosis was in fact enhanced in a BAK-dependent manner. Mitotic apoptosis was accelerated after MARCH5 was ablated in both the presence and absence of MCL1. Cell death was not altered after disrupting other MARCH5-regulated BCL2 family members including NOXA, BIM, and BID. Disruption of the mitochondrial fission factor DRP1, however, reduced mitotic apoptosis in MARCH5-disrupted cells. These data suggest that MARCH5 regulates mitotic apoptosis through MCL1-independent mechanisms including mitochondrial maintenance that can overcome the stabilization of MCL1.

DOI: https://doi.org/10.1038/s41418-022-01080-2
Nat Commun. 2022 Nov 04. 13(1): 6634

Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.

Erminia Donnarumma, Michael Kohlhaas, Elodie Vimont, Etienne Kornobis, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Maryse Moya-Nilges, Christoph Maack, Timothy Wai.

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.

DOI: https://doi.org/10.1038/s41467-022-34316-3