bims-mibica 2024-04-28 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024‒04‒28
thirty-one papers selected by
Kelsey Fisher-Wellman, East Carolina University

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.
Warburg Effect Reshapes Tumor Immunogenicity.
Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
Regulation of mitochondrial fission by fatty acyl-coenzyme A.
PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.
Porphyrin overdrive rewires cancer cell metabolism.
Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
Convergent epigenetic evolution drives relapse in acute myeloid leukemia.
OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death.
Inflammation and mitophagy are mitochondrial checkpoints to aging.
Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.
ACSM1 and ACSM3 regulate fatty acid metabolism to support prostate cancer growth and constrain ferroptosis.
Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.
Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.
Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.
BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma.
Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.
Phenotyping of cancer-associated somatic mutations in the BCL2 transmembrane domain.
Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer.
Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.
Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers.
SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.
THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.
iMPAQT reveals that adequate mitohormesis from TFAM overexpression leads to life extension in mice.
New insights from bidirectional Mendelian randomization: causal relationships between telomere length and mitochondrial DNA copy number in aging biomarkers.
Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis.

bioRxiv. 2024 Apr 15. pii: 2024.04.12.589110. [Epub ahead of print]

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.

James T Hagen, Mclane M Montgomery, Raphael T Aruleba, Brett R Chrest, Thomas D Green, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Myles C Cabot, Joseph M Mclung, Kelsey H Fisher-Wellman.

Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F 1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F 1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

DOI: https://doi.org/10.1101/2024.04.12.589110
EMBO J. 2024 Apr 22.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.

  Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase

DOI:  https://doi.org/10.1038/s44318-024-00101-9
Cancer Res. 2024 Apr 24.

Warburg Effect Reshapes Tumor Immunogenicity.

Jose A Enríquez, María Mittelbrunn.

Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1304
J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.

Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.

  Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.

Keywords:  Metabolism; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI167371
Nat Commun. 2024 Apr 24. 15(1): 3445

Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Jiang-Jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang, Peng Huang.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

DOI: https://doi.org/10.1038/s41467-024-47536-6
Nat Cell Biol. 2024 Apr 23.

Regulation of mitochondrial fission by fatty acyl-coenzyme A.

DOI: https://doi.org/10.1038/s41556-024-01406-x
bioRxiv. 2024 Apr 13. pii: 2024.04.09.588489. [Epub ahead of print]

PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity.

Grigor Varuzhanyan, Chia-Chun Chen, Jack Freeland, Tian He, Wendy Tran, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Gabriella A Dibernardo, Favour N Esedebe, Evan R Abt, Jung Wook Park, Sanaz Memarzadeh, Thomas Graeber, Orian Shirihai, Owen Witte.

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers comprised of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of PGC-1α, a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNC types. PGC-1α correlated tightly with increased expression of the lineage marker ASCL1 through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. PGC-1α overexpression enhanced OXPHOS, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These findings reveal the metabolic heterogeneity among SCNC subtypes and identify PGC-1α-induced OXPHOS as a regulator of SCNC lineage plasticity.

DOI: https://doi.org/10.1101/2024.04.09.588489
Life Sci Alliance. 2024 Jul;pii: e202302547. [Epub ahead of print]7(7):

Porphyrin overdrive rewires cancer cell metabolism.

Swamy R Adapa, Gregory A Hunter, Narmin E Amin, Christopher Marinescu, Andrew Borsky, Elizabeth M Sagatys, Said M Sebti, Gary W Reuther, Gloria C Ferreira, Rays Hy Jiang.

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.

DOI: https://doi.org/10.26508/lsa.202302547
Nature. 2024 Apr 24.

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.

Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.

Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.

DOI: https://doi.org/10.1038/s41586-024-07332-0
Elife. 2024 Apr 22. pii: e93019. [Epub ahead of print]13

Convergent epigenetic evolution drives relapse in acute myeloid leukemia.

Kevin Nuno, Armon Azizi, Thomas Koehnke, Caleb Lareau, Asiri Ediriwickrema, M Ryan Corces, Ansuman T Satpathy, Ravindra Majeti.

  Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

Keywords:  acute myeloid leukemia; cancer biology; epigenetics; genetics; genomics; human; relapse

DOI:  https://doi.org/10.7554/eLife.93019
Cell Death Discov. 2024 Apr 23. 10(1): 190

OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death.

Xiao-Dong Huang, Li Du, Xiao-Chen Cheng, Yu-Xin Lu, Qiao-Wei Liu, Yi-Wu Wang, Ya-Jin Liao, Dong-Dong Lin, Feng-Jun Xiao.

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

DOI: https://doi.org/10.1038/s41420-024-01948-x
Nat Commun. 2024 Apr 20. 15(1): 3375

Inflammation and mitophagy are mitochondrial checkpoints to aging.

Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.

DOI: https://doi.org/10.1038/s41467-024-47840-1
Res Sq. 2024 Apr 08. pii: rs.3.rs-4013392. [Epub ahead of print]

Epstein-Barr-Virus-Driven Cardiolipin Synthesis Sustains Metabolic Remodeling During B-cell Lymphomagenesis.

Haixi You, Larissa Havey, Zhixuan Li, John Asara, Rui Guo.

Epstein-Barr Virus (EBV) is associated with a range of B-cell malignancies, including Burkitt, Hodgkin, post-transplant, and AIDS-related lymphomas. Studies highlight EBV's transformative capability to induce oncometabolism in B-cells to support energy, biosynthetic precursors, and redox equivalents necessary for transition from quiescent to proliferation. Mitochondrial dysfunction presents an intrinsic barrier to EBV B-cell immortalization. Yet, how EBV maintains B-cell mitochondrial function and metabolic fluxes remains unclear. Here we show that EBV boosts cardiolipin(CL) biosynthesis, essential for mitochondrial cristae biogenesis, via EBNA2-induced CL enzyme transactivation. Pharmaceutical and CRISPR genetic analyses underscore the essentiality of CL biosynthesis in EBV-transformed B-cells. Metabolomic and isotopic tracing highlight CL's role in sustaining respiration, one-carbon metabolism, and aspartate synthesis, all vital for EBV-transformed B-cells. Targeting CL biosynthesis destabilizes mitochondrial one-carbon enzymes, causing synthetic lethality when coupled with a SHMT1/2 inhibitor. We demonstrate EBV-induced CL metabolism as a therapeutic target, offering new strategies against EBV-associated B-cell malignancies.

DOI: https://doi.org/10.21203/rs.3.rs-4013392/v1
Cancer Res. 2024 Apr 24.

ACSM1 and ACSM3 regulate fatty acid metabolism to support prostate cancer growth and constrain ferroptosis.

Raj Kumar Shrestha, Zeyad D Nassar, Adrienne R Hanson, Richard Iggo, Scott L Townley, Jonas Dehairs, Chui Yan Mah, Madison Helm, Mohammadreza Alizadeh-Ghodsi, Marie Pickering, Bart Ghesquiere, Matthew J Watt, Lake-Ee Quek, Andrew J Hoy, Wayne D Tilley, Johannes V Swinnen, Lisa M Butler, Luke A Selth.

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, while silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function for medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1489
PLoS Biol. 2024 Apr 26. 22(4): e3002602

Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.

Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.

Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

DOI: https://doi.org/10.1371/journal.pbio.3002602
Leukemia. 2024 Apr 20.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Jiamin Guo, Ralf Buettner, Li Du, Zhenlong Li, Wei Liu, Rui Su, Zhenhua Chen, Yuan Che, Yi Zhang, Rui Ma, Le Xuan Truong Nguyen, Roger E Moore, Pathak Khyatiben, Min-Hsuan Chen, Pirrotte Patrick, Xiwei Wu, Guido Marcucci, Lili Wang, David Horne, Jianjun Chen, Yanzhong Yang, Steven T Rosen.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

DOI: https://doi.org/10.1038/s41375-024-02222-w
Acta Physiol (Oxf). 2024 Apr 26. e14150

Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.

Charlotte A Hoogstraten, Tom J J Schirris, Frans G M Russel.

  A disturbed mitochondrial function contributes to the pathology of many common diseases. These organelles are therefore important therapeutic targets. On the contrary, many adverse effects of drugs can be explained by a mitochondrial off-target effect, in particular, due to an interaction with carrier proteins in the inner membrane. Yet this class of transport proteins remains underappreciated and understudied. The aim of this review is to provide a deeper understanding of the role of mitochondrial carriers in health and disease and their significance as drug targets. We present literature-based evidence that mitochondrial carrier proteins are associated with prevalent diseases and emphasize their potential as drug (off-)target sites by summarizing known mitochondrial drug-transporter interactions. Studying these carriers will enhance our knowledge of mitochondrial drug on- and off-targets and provide opportunities to further improve the efficacy and safety of drugs.

Keywords:  carrier proteins; drugs; efficacy and safety; inner mitochondrial membrane; mitochondria; on‐ and off‐target

DOI:  https://doi.org/10.1111/apha.14150
Cell Rep Med. 2024 Apr 22. pii: S2666-3791(24)00192-7. [Epub ahead of print] 101523

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.

Sanne Bootsma, Mark P G Dings, Job Kesselaar, Roxan F C P A Helderman, Kyah van Megesen, Alexander Constantinides, Leandro Ferreira Moreno, Ellen Stelloo, Enzo M Scutigliani, Bella Bokan, Arezo Torang, Sander R van Hooff, Danny A Zwijnenburg, Valérie M Wouters, Vincent C J van de Vlasakker, Laskarina J K Galanos, Lisanne E Nijman, Adrian Logiantara, Veronique L Veenstra, Sophie Schlingemann, Sterre van Piggelen, Nicole van der Wel, Przemek M Krawczyk, Johannes J Platteeuw, Jurriaan B Tuynman, Ignace H de Hingh, Jan P G Klomp, Arthur Oubrie, Petur Snaebjornsson, Jan Paul Medema, Arlene L Oei, Onno Kranenburg, Clara C Elbers, Kristiaan J Lenos, Louis Vermeulen, Maarten F Bijlsma.

  Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.

Keywords:  HIPEC; copper; elesclomol; mesenchymal cancer cell; mitochondria; molecular subtype; oxidative phosphorylation; peritoneal metastases

DOI:  https://doi.org/10.1016/j.xcrm.2024.101523
Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.

  Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2024.03.030
Sci Rep. 2024 Apr 22. 14(1): 9231

Mitochondrial enzyme FAHD1 reduces ROS in osteosarcoma.

Anne Heberle, Elia Cappuccio, Andreas Andric, Tatjana Kuen, Anna Simonini, Alexander K H Weiss.

This study investigated the impact of overexpressing the mitochondrial enzyme Fumarylacetoacetate hydrolase domain-containing protein 1 (FAHD1) in human osteosarcoma epithelial cells (U2OS) in vitro. While the downregulation or knockdown of FAHD1 has been extensively researched in various cell types, this study aimed to pioneer the exploration of how increased catalytic activity of human FAHD1 isoform 1 (hFAHD1.1) affects human cell metabolism. Our hypothesis posited that elevation in FAHD1 activity would lead to depletion of mitochondrial oxaloacetate levels. This depletion could potentially result in a decrease in the flux of the tricarboxylic acid (TCA) cycle, thereby accompanied by reduced ROS production. In addition to hFAHD1.1 overexpression, stable U2OS cell lines were established overexpressing a catalytically enhanced variant (T192S) and a loss-of-function variant (K123A) of hFAHD1. It is noteworthy that homologs of the T192S variant are present in animals exhibiting increased resistance to oxidative stress and cancer. Our findings demonstrate that heightened activity of the mitochondrial enzyme FAHD1 decreases cellular ROS levels in U2OS cells. However, these results also prompt a series of intriguing questions regarding the potential role of FAHD1 in mitochondrial metabolism and cellular development.

DOI: https://doi.org/10.1038/s41598-024-60012-x
J Infect Dis. 2024 Apr 24. pii: jiae210. [Epub ahead of print]

Hepatitis B virus and hepatitis C virus affect mitochondrial function through different metabolic pathways, explaining virus-specific clinical features of chronic hepatitis.

Sakthi Priya Selvamani, Anis Khan, Enoch S E Tay, Matthew Garvey, Harout Ajoyan, Eve Diefenbach, Brian S Gloss, Thomas Tu, Jacob George, Mark W Douglas.

  BACKGROUND: Hepatitis C virus (HCV) and hepatitis B virus (HBV) cause chronic hepatitis with important clinical differences. HCV causes hepatic steatosis and insulin resistance, while HBV confers increased risk of liver cancer. We hypothesised these differences may be due to virus-specific effects on mitochondrial function.METHODS: Seahorse technology was utilised to investigate effects of virus infection on mitochondrial function. Cell based assays were used to measure mitochondrial membrane potential and quantify pyruvate and lactate. Mass spectrometry was performed on mitochondria isolated from HBV expressing, HCV infected and control cells cultured with isotope-labelled amino acids, to identify proteins with different abundance. Altered expression of key mitochondrial proteins was confirmed by real time PCR and western blot.
RESULTS: Reduced mitochondrial function and ATP production were observed with HCV infection and HBV expression. HCV impairs glycolysis and reduces expression of genes regulating fatty acid oxidation, promoting lipid accumulation. HBV causes lactate accumulation by increasing expression of lactate dehydrogenase A, which converts pyruvate to lactate. In HBV expressing cells there was marked enrichment of pyruvate dehydrogenase kinase, inhibiting conversion of pyruvate to acetyl-CoA and thereby reducing its availability for mitochondrial oxidative phosphorylation.
CONCLUSIONS: HCV and HBV impair mitochondrial function and reduce ATP production. HCV reduces acetyl-CoA availability for energy production by impairing fatty acid oxidation, causing lipid accumulation and hepatic steatosis. HBV has no effect on fatty oxidation but reduces acetyl-CoA availability by disrupting pyruvate metabolism. This promotes lactic acidosis and oxidative stress, increasing the risk of disease progression and liver cancer.

Keywords:  hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; liver cancer; metabolism; mitochondria; steatosis

DOI:  https://doi.org/10.1093/infdis/jiae210
Oncogenesis. 2024 Apr 26. 13(1): 14

Phenotyping of cancer-associated somatic mutations in the BCL2 transmembrane domain.

Diego Leiva, Estefanía Lucendo, Alicia Belén García-Jareño, Mónica Sancho, Mar Orzáez.

The BCL2 family of proteins controls cell death by modulating the permeabilization of the mitochondrial outer membrane through a fine-tuned equilibrium of interactions among anti- and pro-apoptotic members. The upregulation of anti-apoptotic BCL2 proteins represents an unfavorable prognostic factor in many tumor types due to their ability to shift the equilibrium toward cancer cell survival. Furthermore, cancer-associated somatic mutations in BCL2 genes interfere with the protein interaction network, thereby promoting cell survival. A range of studies have documented how these mutations affect the interactions between the cytosolic domains of BCL2 and evaluate the impact on cell death; however, as the BCL2 transmembrane interaction network remains poorly understood, somatic mutations affecting transmembrane regions have been classified as pathogenic-based solely on prediction algorithms. We comprehensively investigated cancer-associated somatic mutations affecting the transmembrane domain of BCL2 proteins and elucidated their effect on membrane insertion, hetero-interactions with the pro-apoptotic protein BAX, and modulation of cell death in cancer cells. Our findings reveal how specific mutations disrupt switchable interactions, alter the modulation of apoptosis, and contribute to cancer cell survival. These results provide experimental evidence to distinguish BCL2 transmembrane driver mutations from passenger mutations and provide new insight regarding selecting precision anti-tumor treatments.

DOI: https://doi.org/10.1038/s41389-024-00516-3
FEBS Open Bio. 2024 Apr 25.

Protein insertion into the inner membrane of mitochondria: routes and mechanisms.

Büsra Kizmaz, Annika Nutz, Annika Egeler, Johannes M Herrmann.

  The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

Keywords:  TIM22 complex; TIM23 complex; carrier proteins; membrane proteins; mitochondria; protein import

DOI:  https://doi.org/10.1002/2211-5463.13806
Mol Med. 2024 Apr 26. 30(1): 56

Ginsenoside Rh2 shifts tumor metabolism from aerobic glycolysis to oxidative phosphorylation through regulating the HIF1-α/PDK4 axis in non-small cell lung cancer.

Xiyu Liu, Jingjing Li, Qingqing Huang, Mingming Jin, Gang Huang.

  BACKGROUND: Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function.METHOD: We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR.
RESULT: Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor's aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier.
CONCLUSION: G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.

Keywords:  Ginsenoside Rh2; Glycolysis; NSCLC; Oxidative phosphorylation; PDK4

DOI:  https://doi.org/10.1186/s10020-024-00813-y
Mol Biol Rep. 2024 Apr 24. 51(1): 567

Beta hydroxybutyrate induces lung cancer cell death, mitochondrial impairment and oxidative stress in a long term glucose-restricted condition.

Farzad Izak Shirian, Milad Karimi, Maryam Alipour, Siamak Salami, Mitra Nourbakhsh, Samira Nekufar, Nahid Safari-Alighiarloo, Masoumeh Tavakoli-Yaraki.

  BACKGROUND: Metabolic plasticity gives cancer cells the ability to shift between signaling pathways to facilitate their growth and survival. This study investigates the role of glucose deprivation in the presence and absence of beta-hydroxybutyrate (BHB) in growth, death, oxidative stress and the stemness features of lung cancer cells.METHODS AND RESULTS: A549 cells were exposed to various glucose conditions, both with and without beta-hydroxybutyrate (BHB), to evaluate their effects on apoptosis, mitochondrial membrane potential, reactive oxygen species (ROS) levels using flow cytometry, and the expression of CD133, CD44, SOX-9, and β-Catenin through Quantitative PCR. The activity of superoxide dismutase, glutathione peroxidase, and malondialdehyde was assessed using colorimetric assays. Treatment with therapeutic doses of BHB triggered apoptosis in A549 cells, particularly in cells adapted to glucose deprivation. The elevated ROS levels, combined with reduced levels of SOD and GPx, indicate that oxidative stress contributes to the cell arrest induced by BHB. Notably, BHB treatment under glucose-restricted conditions notably decreased CD133 expression, suggesting a potential inhibition of cell survival through the downregulation of CD133 levels. Additionally, the simultaneous decrease in mitochondrial membrane potential and increase in ROS levels indicate the potential for creating oxidative stress conditions to impede tumor cell growth in such environmental settings.
CONCLUSION: The induced cell death, oxidative stress and mitochondria impairment beside attenuated levels of cancer stem cell markers following BHB administration emphasize on the distinctive role of metabolic plasticity of cancer cells and propose possible therapeutic approaches to control cancer cell growth through metabolic fuels.

Keywords:  A459 cells; Apoptosis; Beta-hydroxybutyrate; Mitochondria membrane potential (ΔΨm); Reactive oxygen species (ROS); Stemness

DOI:  https://doi.org/10.1007/s11033-024-09501-w
Cancer Cell. 2024 Apr 23. pii: S1535-6108(24)00128-4. [Epub ahead of print]

Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers.

Sarah T Diepstraten, Yin Yuan, John E La Marca, Savannah Young, Catherine Chang, Lauren Whelan, Aisling M Ross, Karla C Fischer, Giovanna Pomilio, Rhiannon Morris, Angela Georgiou, Veronique Litalien, Fiona C Brown, Andrew W Roberts, Andreas Strasser, Andrew H Wei, Gemma L Kelly.

  TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

Keywords:  BH3-mimetic drugs; STING; acute myeloid leukemia; apoptosis; blood cancer; lymphoma; p53

DOI:  https://doi.org/10.1016/j.ccell.2024.04.004
Sci Rep. 2024 04 20. 14(1): 9104

SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.

Hannah Åbacka, Samuele Masoni, Giulio Poli, Peng Huang, Francesco Gusso, Carlotta Granchi, Filippo Minutolo, Tiziano Tuccinardi, Anna K Hagström-Andersson, Karin Lindkvist-Petersson.

  Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common among children. AML is characterized by aberrant proliferation of myeloid blasts in the bone marrow and impaired normal hematopoiesis. Despite the introduction of new drugs and allogeneic bone marrow transplantation, patients have poor overall survival rate with relapse as the major challenge, driving the demand for new therapeutic strategies. AML patients with high expression of the very long/long chain fatty acid transporter CD36 have poorer survival and very long chain fatty acid metabolism is critical for AML cell survival. Here we show that fatty acids are transferred from human primary adipocytes to AML cells upon co-culturing. A drug-like small molecule (SMS121) was identified by receptor-based virtual screening and experimentally demonstrated to target the lipid uptake protein CD36. SMS121 reduced the uptake of fatty acid into AML cells that could be reversed by addition of free fatty acids and caused decreased cell viability. The data presented here serves as a framework for the development of CD36 inhibitors to be used as future therapeutics against AML.

Keywords:  AML; Acute myeloid leukemia; Adipocyte; CD36; Fatty acid

DOI:  https://doi.org/10.1038/s41598-024-58689-1
FEBS Lett. 2024 Apr 25.

THAP3 recruits SMYD3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma.

Zi-Hao Wang, Jingyi Wang, Fuchen Liu, Sijun Sun, Quan Zheng, Xiaotian Hu, Zihan Yin, Chengmei Xie, Haiyan Wang, Tianshi Wang, Shengjie Zhang, Yi-Ping Wang.

  Mitochondria harbor the oxidative phosphorylation (OXPHOS) system to sustain cellular respiration. However, the transcriptional regulation of OXPHOS remains largely unexplored. Through the cancer genome atlas (TCGA) transcriptome analysis, transcription factor THAP domain-containing 3 (THAP3) was found to be strongly associated with OXPHOS gene expression. Mechanistically, THAP3 recruited the histone methyltransferase SET and MYND domain-containing protein 3 (SMYD3) to upregulate H3K4me3 and promote OXPHOS gene expression. The levels of THAP3 and SMYD3 were altered by metabolic cues. They collaboratively supported liver cancer cell proliferation and colony formation. In clinical human liver cancer, both of them were overexpressed. THAP3 positively correlated with OXPHOS gene expression. Together, THAP3 cooperates with SMYD3 to epigenetically upregulate cellular respiration and liver cancer cell proliferation.

Keywords:  SET and MYND domain‐containing protein 3; THAP domain‐containing 3; histone H3 lysine 4 tri‐methylation; liver cancer; mitochondrial respiration; oxidative phosphorylation

DOI:  https://doi.org/10.1002/1873-3468.14889
Life Sci Alliance. 2024 Jul;pii: e202302498. [Epub ahead of print]7(7):

iMPAQT reveals that adequate mitohormesis from TFAM overexpression leads to life extension in mice.

Ko Igami, Hiroki Kittaka, Mikako Yagi, Kazuhito Gotoh, Yuichi Matsushima, Tomomi Ide, Masataka Ikeda, Saori Ueda, Shin-Ichiro Nitta, Manami Hayakawa, Keiichi I Nakayama, Masaki Matsumoto, Dongchon Kang, Takeshi Uchiumi.

Mitochondrial transcription factor A, TFAM, is essential for mitochondrial function. We examined the effects of overexpressing the TFAM gene in mice. Two types of transgenic mice were created: TFAM heterozygous (TFAM Tg) and homozygous (TFAM Tg/Tg) mice. TFAM Tg/Tg mice were smaller and leaner notably with longer lifespans. In skeletal muscle, TFAM overexpression changed gene and protein expression in mitochondrial respiratory chain complexes, with down-regulation in complexes 1, 3, and 4 and up-regulation in complexes 2 and 5. The iMPAQT analysis combined with metabolomics was able to clearly separate the metabolomic features of the three types of mice, with increased degradation of fatty acids and branched-chain amino acids and decreased glycolysis in homozygotes. Consistent with these observations, comprehensive gene expression analysis revealed signs of mitochondrial stress, with elevation of genes associated with the integrated and mitochondrial stress responses, including Atf4, Fgf21, and Gdf15. These found that mitohormesis develops and metabolic shifts in skeletal muscle occur as an adaptive strategy.

DOI: https://doi.org/10.26508/lsa.202302498
Aging (Albany NY). 2024 Apr 24. 16

New insights from bidirectional Mendelian randomization: causal relationships between telomere length and mitochondrial DNA copy number in aging biomarkers.

Xinyu Yan, Peixuan Yang, Yani Li, Ting Liu, Yawen Zha, Ting Wang, Jingjing Zhang, Zhijun Feng, Minying Li.

  Mitochondrial DNA (mtDNA) copy number and telomere length (TL) are dynamic factors that have been linked to the aging process in organisms. However, the causal relationship between these variables remains uncertain. In this research, instrumental variables (IVs) related to mtDNA copy number and TL were obtained from publicly available genome-wide association studies (GWAS). Through bidirectional Mendelian randomization (MR) analysis, we examined the potential causal relationship between these factors. The forward analysis, with mtDNA copy number as the exposure and TL as the outcome, did not reveal a significant effect (B=-0.004, P>0.05). On the contrary, upon conducting a reverse analysis, it was found that there exists a positive causal relationship (B=0.054, P<0.05). Sensitivity analyses further confirmed the reliability of these results. The outcomes of this study indicate a one-way positive causal relationship, indicating that telomere shortening in the aging process may lead to a decrease in mtDNA copy number, providing new perspectives on their biological mechanisms.

Keywords:  bidirectional two-sample Mendelian randomization; causal relationship; mitochondrial DNA copy number; telomere length

DOI:  https://doi.org/10.18632/aging.205765
Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2319833121

Sirt2 inhibition improves gut epithelial barrier integrity and protects mice from colitis.

Dan Hou, Tao Yu, Xuan Lu, Jun Young Hong, Min Yang, Yanlin Zi, Thanh Tu Ho, Hening Lin.

  Sirt2 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacylase that can remove both acetyl group and long-chain fatty acyl groups from lysine residues of many proteins. It was reported to affect inflammatory bowel disease (IBD) symptoms in a mouse model. However, conflicting roles were reported, with genetic knockout aggravating while pharmacological inhibition alleviating IBD symptoms. These seemingly conflicting reports cause confusion and deter further efforts in developing Sirt2 inhibitors as a potential treatment strategy for IBD. We investigated these conflicting reports and elucidated the role of Sirt2 in the mouse model of IBD. We essentially replicated these conflicting results and confirmed that Sirt2 inhibitors' protective effect is not through off-targets as two very different Sirt2 inhibitors (TM and AGK2) showed similar protection in the IBD mouse model. We believe that the differential effects of inhibitors and knockout are due to the fact that the Sirt2 inhibitors only inhibit some but not all the activities of Sirt2. This hypothesis is confirmed by the observation that a PROTAC degrader of Sirt2 did not protect mice in the IBD model, similar to Sirt2 knockout. Our study provides an interesting example where genetic knockout and pharmacological inhibition do not align and emphasizes the importance of developing substrate-dependent inhibitors. Importantly, we showed that the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6-mediated endocytosis of E-cadherin, a protein important for the intestinal epithelial integrity. This mechanistic understanding further supports Sirt2 as a promising therapeutic target for treating IBD.

Keywords:  Arf6; E-cadherin; inflammatory bowel disease; sirtuins; substrate-dependent inhibition

DOI:  https://doi.org/10.1073/pnas.2319833121