bims-minimp 2022-07-24 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–07–24
eleven papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.
DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer's Disease.
Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.
Structural overview of the translocase of the mitochondrial outer membrane complex.
The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity.
Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants.
Mitochondrial genome undergoes de novo DNA methylation that protects mtDNA against oxidative damage during the peri-implantation window.
Ischemic damage to every segment of the oxidative phosphorylation cascade elevates ETC driving force and ROS production in cardiac mitochondria.
Inhibition of respiratory complex I by 6-ketocholestanol: Relevance to recoupling action in mitochondria.
Mechanisms and consequences of endothelial cell senescence.
Prohibitins: A Key Link between Mitochondria and Nervous System Diseases.

EMBO J. 2022 Jul 20. e110784

AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.

Silja Lucia Salscheider, Sarah Gerlich, Alfredo Cabrera-Orefice, Esra Peker, Robin Alexander Rothemann, Lena Maria Murschall, Yannik Finger, Karolina Szczepanowska, Zeinab Alsadat Ahmadi, Sergio Guerrero-Castillo, Alican Erdogan, Mark Becker, Muna Ali, Markus Habich, Carmelina Petrungaro, Nele Burdina, Guenter Schwarz, Merlin Klußmann, Ines Neundorf, David A Stroud, Michael T Ryan, Aleksandra Trifunovic, Ulrich Brandt, Jan Riemer.

  The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.

Keywords:  AIFM1; MIA40-CHCHD4; NDUFS5; complex I; mitochondrial disulfide relay

DOI:  https://doi.org/10.15252/embj.2022110784
J Alzheimers Dis. 2022 Jul 11.

DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer's Disease.

Genper Chi-Ngai Wong, Kim Hei-Man Chow.

  Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer's disease. Senescent cells accumulated in the aging and Alzheimer's disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence.

Keywords:  Alzheimer’s disease; brain aging; cell cycle re-entry; neuronal cell senescence; persistent DNA damage response

DOI:  https://doi.org/10.3233/JAD-220203
Nature. 2022 Jul 20.

Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I.

Aida Rodríguez-Nuevo, Ariadna Torres-Sanchez, Juan M Duran, Cristian De Guirior, Maria Angeles Martínez-Zamora, Elvan Böke.

Oocytes form before birth and remain viable for several decades before fertilization1. Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age2. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival3-5. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.

DOI: https://doi.org/10.1038/s41586-022-04979-5
Biophys Physicobiol. 2022 ;19 e190022

Structural overview of the translocase of the mitochondrial outer membrane complex.

Yuhei Araiso, Toshiya Endo.

  Most mitochondrial proteins are synthesized as precursor proteins (preproteins) in the cytosol and imported into mitochondria. The translocator of the outer membrane (TOM) complex functions as a main entry gate for the import of mitochondrial proteins. The TOM complex is a multi-subunit membrane protein complex composed of a β-barrel channel Tom40 and six single-pass membrane proteins. Recent cryo-EM studies have revealed high-resolution structures of the yeast and human TOM complexes, which enabled us to discuss the mechanism of protein import at an amino-acid residue level. The cryo-EM structures show that two Tom40 β-barrels are surrounded by two sets of small Tom subunits to form a dimeric structure. The intermembrane space (IMS) domains of Tom40, Tom22, and Tom7 form a binding site for presequence-containing preproteins in the middle of the dimer to achieve their efficient transfer of to the downstream translocase, the TIM23 complex. The N-terminal segment of Tom40 spans the channel from the cytosol to the IMS to interact with Tom5 at the periphery of the dimer, where downstream components of presequence-lacking preproteins are recruited. Structure-based biochemical analyses together with crosslinking experiments revealed that each Tom40 channel possesses two distinct paths and exit sites for protein translocation of different sets of mitochondrial preproteins. Here we summarize the current knowledge on the structural features, protein translocation mechanisms, and remaining questions for the TOM complexes, with particular emphasis on their determined cryo-EM structures. This article is an extended version of the Japanese article, Structural basis for protein translocation by the translocase of the outer mitochondrial membrane, published in SEIBUTSU BUTSURI Vol. 60, p. 280-283 (2020).

Keywords:  Cryo-EM; TOM complex preprotein; mitochondria; protein translocation

DOI:  https://doi.org/10.2142/biophysico.bppb-v19.0022
Sci Adv. 2022 Jul 22. 8(29): eabo0155

The ER protein Creld regulates ER-mitochondria contact dynamics and respiratory complex 1 activity.

Marie Paradis, Nicole Kucharowski, Gabriela Edwards Faret, Santiago José Maya Palacios, Christian Meyer, Birgit Stümpges, Isabell Jamitzky, Julia Kalinowski, Christoph Thiele, Reinhard Bauer, Achim Paululat, Julia Sellin, Margret Helene Bülow.

Dynamic contacts are formed between endoplasmic reticulum (ER) and mitochondria that enable the exchange of calcium and phospholipids. Disturbed contacts between ER and mitochondria impair mitochondrial dynamics and are a molecular hallmark of Parkinson's disease, which is also characterized by impaired complex I activity and dopaminergic neuron degeneration. Here, we analyzed the role of cysteine-rich with EGF-like domain (Creld), a poorly characterized risk gene for Parkinson's disease, in the regulation of mitochondrial dynamics and function. We found that loss of Creld leads to mitochondrial hyperfusion and reduced ROS signaling in Drosophila melanogaster, Xenopus tropicalis, and human cells. Creld fly mutants show differences in ER-mitochondria contacts and reduced respiratory complex I activity. The resulting low-hydrogen peroxide levels are linked to disturbed neuronal activity and lead to impaired locomotion, but not neurodegeneration, in Creld mutants. We conclude that Creld regulates ER-mitochondria communication and thereby hydrogen peroxide formation, which is required for normal neuron function.

DOI: https://doi.org/10.1126/sciadv.abo0155
Mech Ageing Dev. 2022 Jul 18. pii: S0047-6374(22)00090-2. [Epub ahead of print] 111708

Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants.

Jin Young Sung, Seul Gi Kim, Young Jin Kang, Hyoung Chul Choi.

  The senescence of vascular smooth muscle cells (VSMCs) is an important cause of cardiovascular disease such as atherosclerosis and hypertension. These senescence may be triggered by many factors, such as oxidative stress, inflammation, DNA damage, and senescence-associated secretory phenotypes (SASPs). Mitochondrial oxidative stress induces cellular senescence, but the mechanisms by which mitochondrial reactive oxygen species (mtROS) regulates cellular senescence are still largely unknown. Here, we investigated the mechanism responsible for the anti-aging effect of metformin by examining links between VSMC senescence and mtROS in in vitro and in vivo. Metformin was found to increase p-AMPK (Ser485), but to decrease senescence-associated phenotypes and protein levels of senescence markers during ADR-induced VSMC senescence. Importantly, metformin decreased mtROS by inducing the deacetylation of superoxide dismutase 2 (SOD2) by increasing SIRT3 expression. Moreover, AMPK depletion reduced the expression of SIRT3 and increased the expression of acetylated SOD2 despite metformin treatment, suggesting AMPK activation by metformin is required to protect against mitochondrial oxidative stress by SIRT3. This study provides mechanistic evidence that metformin acts as an anti-aging agent and alleviates VSMC senescence by upregulating mitochondrial antioxidant induced p-AMPK (Ser485)-dependent SIRT3 expression, which suggests metformin has therapeutic potential for the treatment of age-associated vascular disease.

Keywords:  Metformin; SIRT3; SOD2 acetylation; VSMC senescence; mitochondrial ROS; p-AMPK (Ser485)

DOI:  https://doi.org/10.1016/j.mad.2022.111708
Proc Natl Acad Sci U S A. 2022 Jul 26. 119(30): e2201168119

Mitochondrial genome undergoes de novo DNA methylation that protects mtDNA against oxidative damage during the peri-implantation window.

Yuan Yue, Likun Ren, Chao Zhang, Kai Miao, Kun Tan, Qianying Yang, Yupei Hu, Guangyin Xi, Gang Luo, Mingyao Yang, Jingyu Zhang, Zhuocheng Hou, Lei An, Jianhui Tian.

  Mitochondrial remodeling during the peri-implantation stage is the hallmark event essential for normal embryogenesis. Among the changes, enhanced oxidative phosphorylation is critical for supporting high energy demands of postimplantation embryos, but increases mitochondrial oxidative stress, which in turn threatens mitochondrial DNA (mtDNA) stability. However, how mitochondria protect their own histone-lacking mtDNA, during this stage remains unclear. Concurrently, the mitochondrial genome gain DNA methylation by this stage. Its spatiotemporal coincidence with enhanced mitochondrial stress led us to ask if mtDNA methylation has a role in maintaining mitochondrial genome stability. Herein, we report that mitochondrial genome undergoes de novo mtDNA methylation that can protect mtDNA against enhanced oxidative damage during the peri-implantation window. Mitochondrial genome gains extensive mtDNA methylation during transition from blastocysts to postimplantation embryos, thus establishing relatively hypermethylated mtDNA from hypomethylated state in blastocysts. Mechanistic study revealed that DNA methyltransferase 3A (DNMT3A) and DNMT3B enter mitochondria during this process and bind to mtDNA, via their unique mitochondrial targeting sequences. Importantly, loss- and gain-of-function analyses indicated that DNMT3A and DNMT3B are responsible for catalyzing de novo mtDNA methylation, in a synergistic manner. Finally, we proved, in vivo and in vitro, that increased mtDNA methylation functions to protect mitochondrial genome against mtDNA damage induced by increased mitochondrial oxidative stress. Together, we reveal mtDNA methylation dynamics and its underlying mechanism during the critical developmental window. We also provide the functional link between mitochondrial epigenetic remodeling and metabolic changes, which reveals a role for nuclear-mitochondrial crosstalk in establishing mitoepigenetics and maintaining mitochondrial homeostasis.

Keywords:  DNMT3A/3B; de novo DNA methylation; mitochondrial DNA; mitochondrial oxidative damage; peri-implantation

DOI:  https://doi.org/10.1073/pnas.2201168119
Am J Physiol Heart Circ Physiol. 2022 Jul 22.

Ischemic damage to every segment of the oxidative phosphorylation cascade elevates ETC driving force and ROS production in cardiac mitochondria.

Sarah Kuzmiak-Glancy, Brian Glancy, Matthew W Kay.

  Myocardial ischemia has long-lasting negative impacts on cardiomyocyte mitochondrial ATP production. However, the location(s) of damage to the oxidative phosphorylation pathway responsible for altered mitochondrial function is unclear. Mitochondrial reactive oxygen species (ROS) production increases following ischemia, but the specific factors controlling this increase are unknown. To determine how ischemia affects the mitochondrial energy conversion cascade and ROS production, mitochondrial driving forces (redox potential and membrane potential (ΔΨ)) were measured at resting, intermediate, and maximal respiration rates in mitochondria isolated from rat hearts after 60 minutes of control flow (Control) or no-flow ischemia (Ischemia). The effective activities of the dehydrogenase enzymes, the electron transport chain (ETC), and ATP synthesis and transport were computed using the driving forces and flux. Ischemia lowered maximal mitochondrial respiration rates and diminished the responsiveness of respiration to both redox potential and ΔΨ. Ischemia decreased the activities of every component of the oxidative phosphorylation pathway: the dehydrogenase enzymes, the ETC, and ATP synthesis and transport. ROS production was linearly related to driving force down the ETC; however, Ischemia mitochondria demonstrated a greater driving force down the ETC and higher ROS production. Overall, results indicate that ischemia ubiquitously damages the oxidative phosphorylation pathway, reduces mitochondrial sensitivity to driving forces, and augments the propensity for electrons to leak from the ETC. These findings underscore that strategies to improve mitochondrial function following ischemia must target the entire mitochondrial energy conversion cascade.

Keywords:  cardiac ischemia; metabolic control; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1152/ajpheart.00129.2022
Biochim Biophys Acta Bioenerg. 2022 Jul 16. pii: S0005-2728(22)00063-9. [Epub ahead of print]1863(7): 148594

Inhibition of respiratory complex I by 6-ketocholestanol: Relevance to recoupling action in mitochondria.

Vera G Grivennikova, Ljudmila S Khailova, Tatyana V Zharova, Elena A Kotova, Yuri N Antonenko.

  6-Ketocholestanol (kCh) is known as a mitochondrial recoupler, i.e. it abolishes uncoupling of mitochondria by such potent agents as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and 3,5-di(tert-butyl)-4-hydroxybenzylidenemalononitril (SF6847) [Starkov et al., 1997]. Here, we report data on the kCh-induced inhibition of both NADH-oxidase and NADH-ubiquinone oxidoreductase activities of the respiratory complex I in bovine heart submitochondrial particles (SMP). Based on the absence of such inhibition with hexaammineruthenium (III) (HAR) as the complex I electron acceptor, the kCh effect could be associated with the ubiquinone-binding centre of this respiratory enzyme. In isolated rat liver mitochondria (RLM), kCh inhibited oxygen consumption with the glutamate/malate, substrates of NAD-linked dehydrogenases, while no inhibition of RLM respiration was observed with succinate, in agreement with the absence of the kCh effect on the succinate oxidase activity in SMP. Three kCh analogs (cholesterol, 6α-hydroxycholesterol, and 5α,6α-epoxycholesterol) exhibited no effect on the NADH oxidase activities in both SMP and RLM. Importantly, the kCh analogs were ineffective in the recoupling of RLM treated with CCCP or SF6847. Therefore, interaction of kCh with the complex I may be involved in the kCh-mediated mitochondrial recoupling.

Keywords:  6-Ketocholestanol; Mitochondria; Recoupling; Respiratory complex I; Submitochondrial particles; Uncoupler

DOI:  https://doi.org/10.1016/j.bbabio.2022.148594
Nat Rev Cardiol. 2022 Jul 19.

Mechanisms and consequences of endothelial cell senescence.

Samuel I Bloom, Md Torikul Islam, Lisa A Lesniewski, Anthony J Donato.

Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.

DOI: https://doi.org/10.1038/s41569-022-00739-0
Oxid Med Cell Longev. 2022 ;2022 7494863

Prohibitins: A Key Link between Mitochondria and Nervous System Diseases.

Tianlin Jiang, Jiahua Wang, Chao Li, Guiyun Cao, Xiaohong Wang.

Prohibitins (PHBs) are conserved proteins in eukaryotic cells, which are mainly located in the inner mitochondrial membrane (IMM), cell nucleus, and cell membrane. PHBs play crucial roles in various cellular functions, including the cell cycle regulation, tumor suppression, immunoglobulin M receptor binding, and aging. In addition, recent in vitro and in vivo studies have revealed that PHBs are important in nervous system diseases. PHBs can prevent apoptosis, inflammation, mitochondrial dysfunction, and autophagy in neurological disorders through different molecules and pathways, such as OPA-1, PINK1/Parkin, IL6/STAT3, Tau, NO, LC3, and TDP43. Therefore, PHBs show great promise in the protection of neurological disorders. This review summarizes the relevant studies on the relationship between PHBs and neurological disorders and provides an update on the molecular mechanisms of PHBs in nervous system diseases.

DOI: https://doi.org/10.1155/2022/7494863