bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–11–24
fiveteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Textbook oxidative phosphorylation needs to be rewritten.
  2. An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
  3. Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.
  4. H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
  5. The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer.
  6. BCL-2 inhibition in acute myeloid leukemia: resistance and combinations.
  7. Nanotube-mediated mitochondrial transfer: power to the T cells!
  8. Anti-leukemia efficacy of the dual BCL2/BCL-XL inhibitor AZD0466 in acute lymphoblastic leukemia preclinical models.
  9. Construction of molecular subtype and prognostic model for gastric cancer based on nucleus-encoded mitochondrial genes.
  10. An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.
  11. Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms.
  12. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  13. Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
  14. Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.
  15. Electrogenic and non-electrogenic ion antiporters participate in controling membrane potential.
  1. Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]
    Textbook oxidative phosphorylation needs to be rewritten.
    Alicia J Kowaltowski, Fernando Abdulkader.
      Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
    Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange
    DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
  2. bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]
    An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.
    DOI:  https://doi.org/10.1101/2024.10.31.621317
  3. Haematologica. 2024 Nov 21.
    Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.
    Yael Morgenstern, JongBok Lee, Yoosu Na, Brandon Y Lieng, Nicholas S Ly, William D Gwynne, Rose Hurren, Li Ma, Dakai Ling, Marcela Gronda, Andrea Arruda, Avraham Frisch, Tsila Zuckerman, Yishai Ofran, Mark D Minden, Li Zhang, Catherine O'Brien, Andrew T Quaile, J Rafael Montenegro-Burke, Aaron D Schimmer.
      Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.
    DOI:  https://doi.org/10.3324/haematol.2024.286018
  4. bioRxiv. 2024 Nov 03. pii: 2024.10.30.621162. [Epub ahead of print]
    H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
    David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.
      Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.
    Significance Statement: Hydrogen sulfide is a product of host as well as gut microbial metabolism and has the dual capacity for activating respiration as a substrate, and inhibiting it at the level of complex IV. In this study, we report that chronic albeit low-level sulfide exposure elicits profound changes in mitochondrial architecture in cultured human cells. Disruption of mitochondrial networks is reversed upon removal of sulfide from the growth chamber atmosphere. Sulfide-dependent depolarization of the inner mitochondrial membrane is associated with loss of cristae and respiratory supercomplexes. Our study reveals the potential for sulfide to be an endogenous regulator of mitochondrial ultrastructure and function via modulation of electron flux and for this process to be corrupted in sulfide dysregulated diseases.
    DOI:  https://doi.org/10.1101/2024.10.30.621162
  5. Transl Med Commun. 2024 ;pii: 21. [Epub ahead of print]9(1):
    The combined treatment with ketogenic diet and metformin slows tumor growth in two mouse models of triple negative breast cancer.
    Karen Schmidt, Amber Thatcher, Albert Grobe, Pamela Broussard, Linda Hicks, Haiwei Gu, Lesley G Ellies, Dorothy D Sears, Leonid Kalachev, Eugene Kroll.
       Background: Many tumors contain hypoxic microenvironments caused by inefficient tumor vascularization. Hypoxic tumors have been shown to resist conventional cancer therapies. Hypoxic cancer cells rely on glucose to meet their energetic and anabolic needs to fuel uncontrolled proliferation and metastasis. This glucose dependency is linked to a metabolic shift in response to hypoxic conditions.
    Methods: To leverage the glucose dependency of hypoxic tumor cells, we assessed the effects of a mild reduction in systemic glucose by controlling both dietary carbohydrates with a ketogenic diet and endogenous glucose production by using metformin on two mouse models of triple-negative breast cancer (TNBC).
    Results: Here, we showed that animals with TNBC treated with the combination regimen of ketogenic diet and metformin (a) had their tumor burden lowered by two-thirds, (b) displayed 38% slower tumor growth, and (c) showed 36% longer latency, compared to the animals treated with a ketogenic diet or metformin alone. As a result, lowering systemic glucose by this combined dietary and pharmacologic approach improved overall survival in our mouse TNBC models by 31 days, approximately equivalent to 3 years of life extension in human terms.
    Conclusion: This preclinical study demonstrates that reducing systemic glucose by combining a ketogenic diet and metformin significantly inhibits tumor proliferation and increases overall survival. Our findings suggest a possible treatment for a broad range of hypoxic and glycolytic tumor types that can augment existing treatment options to improve patient outcomes.
    Keywords:  Glycolytic tumor; Hypoxic tumor; Ketogenic diet; Metformin; Systemic glucose limitation
    DOI:  https://doi.org/10.1186/s41231-024-00178-8
  6. Expert Rev Hematol. 2024 Nov 18. 1-12
    BCL-2 inhibition in acute myeloid leukemia: resistance and combinations.
    Qi Zhang Tatarata, Zhe Wang, Marina Konopleva.
       INTRODUCTION: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response.
    AREAS COVERED: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge.
    EXPERT OPINION: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.
    Keywords:  AML; Venetoclax; metabolism; mitochondria; resistance; signaling pathway
    DOI:  https://doi.org/10.1080/17474086.2024.2429604
  7. Trends Immunol. 2024 Nov 20. pii: S1471-4906(24)00272-2. [Epub ahead of print]
    Nanotube-mediated mitochondrial transfer: power to the T cells!
    Cosima T Baldari.
      The success of T cell-based immunotherapies is limited by exhaustion, which is associated with mitochondrial dysfunction. Baldwin and colleagues show that bone marrow stromal cells (BMSCs) use nanotubes to transfer mitochondria to T cells, which increases mitochondria mass and fitness and boosts antitumor efficacy. The results pave the way to organelle-based therapies against cancer.
    DOI:  https://doi.org/10.1016/j.it.2024.11.001
  8. Blood Adv. 2024 Nov 19. pii: bloodadvances.2024013423. [Epub ahead of print]
    Anti-leukemia efficacy of the dual BCL2/BCL-XL inhibitor AZD0466 in acute lymphoblastic leukemia preclinical models.
    Sankaranarayanan Kannan, Yizhen Li, Natalia Baran, Xu Yang, Sanaz Ghotbaldini, Qi Zhang Tatarata, Satoshi Yoshimura, Zhenhua Li, Yu-Chih Hsiao, Srividya B Balachander, Courtney L Andersen, Justin Cidado, Jiyang Yu, Nitin Jain, Jun J Yang, Marina Y Konopleva.
      The upregulation of BCL2 and BCL-XL, two proteins in the BCL2 family of proteins, leads to a disproportional expression of pro-death and pro-survival proteins in favor of leukemia survival, tumorigenesis, and chemoresistance. In different subsets of acute lymphoblastic leukemia (ALL), the proportion of these two proteins varies, and their potential as therapeutic targets needs detailed characterization. Here, we investigated BCL2 and BCL-XL, the genes that encode BCL2 and BCL-XL, and their expression differences between B-cell acute lymphoblastic leukemia (B-ALL) and T-cell ALL (T-ALL). We also evaluated the therapeutic potential of targeting these proteins with AZD0466, a novel drug-dendrimer conjugate of the BCL2/-XL inhibitor AZD4320, and with BCL2 inhibitor venetoclax (ABT-199). Gene expression and activity analyses supported by the protein expression patterns in ALL cell lines and primary samples demonstrated increased levels of BCL2 expression in B-ALL with high sensitivity to venetoclax or AZD4320. In contrast, strong BCL-XL expression and sensitivity to dual BCL2/-XL inhibition was observed specifically in T-ALL samples. This observation was confirmed by BH3 profiling, demonstrating BCL2/-XL co-dependence in T-ALL and BCL2 dependence in B-ALL. In a mouse model of T-ALL, AZD0466 but not venetoclax reduced leukemic burden and prolonged survival without significant toxicities. Our findings therefore suggest that the novel dual BCL2/-XL inhibitor AZD0466 outperforms single BCL2 inhibition by venetoclax in T-ALL. These findings facilitate the translation of dual BCL2/-XL inhibitors into ALL clinical trials, either alone or in combination with standard- of- care chemotherapy and immune therapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013423
  9. Sci Rep. 2024 11 18. 14(1): 28491
    Construction of molecular subtype and prognostic model for gastric cancer based on nucleus-encoded mitochondrial genes.
    Xu Wang, Sainan Li, Yuhuan Shen, Li Cao, Yajuan Lu, Jinghao Cao, Yingchao Liu, Aoli Deng, Jiyun Yang, Tongtong Wang.
      Gastric cancer (GC) is a common digestive system cancer, characterized by a significant mortality rate. Mitochondria is an indispensable organelle in eukaryotic cells. It was previously revealed that a series of nucleus-encoded mitochondrial genes (NMG) mutations and dysfunctions potentially contribute to the initiation and progression of GC. However, the correlation between NMG mutations and survival outcomes for GC patients is still unclear. In this study, NMG expression profile and clinical information in GC samples were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Through consistent clustering and functional enrichment analysis, we have identified three NMG clusters and three gene clusters that are associated with patterns of immune cell infiltration. Prognostic genes were identified through Univariate Cox regression analysis. The principal component analysis was conducted to set up a scoring system. Subsequently, the Single‑cell RNA sequencing (scRNA-seq) data of GC patients and cancer cell drug sensitivity data were retrieved from the GEO database. Patients with high NMG scores exhibited increased microsatellite instability status and a heightened tumor mutation rate compared to those with low NMG scores. Survival analysis revealed that GC samples with high NMG scores could achieve a better prognosis. Additionally, These patients were observed to be more responsive to immunotherapy. Moreover, we delved into prognostic genes at the level of single cells, revealing that MRPL4 and MRPL37 exhibit high expression in epithelial cells, while TPM1 demonstrates high expression in tissue stem cells. Utilizing cancer cell drug sensitivity data from the Drug Sensitivity in Cancer (GDSC) database, we noted a heightened sensitivity to chemotherapy in the high NMG group. Furthermore, we discovered a significant enrichment of cuproptosis-related genes in clusters with high NMG scores. Consequently, employing the scoring system could facilitate the prediction of GC patients' sensitivity to cuproptosis-induced therapy. Our study confirmed the potency of this scoring system as a therapeutic response biomarker for gastric cancer, potentially informing clinical treatment strategies.
    Keywords:  Gastric cancer; Immunotherapy; Nucleus-encoded mitochondrial genes; Tumor microenvironment; Tumor mutational burden
    DOI:  https://doi.org/10.1038/s41598-024-78729-0
  10. Clin Transl Med. 2024 Nov;14(11): e70030
    An AMP-activated protein kinase-PGC-1α axis mediates metabolic plasticity in glioblastoma.
    Benedikt Sauer, Jan Kueckelhaus, Nadja I Lorenz, Süleyman Bozkurt, Dorothea Schulte, Jan-Béla Weinem, Mohaned Benzarti, Johannes Meiser, Hans Urban, Giulia Villa, Patrick N Harter, Christian Münch, Johannes Rieger, Joachim P Steinbach, Dieter Henrik Heiland, Michael W Ronellenfitsch.
      Glioblastoma, the most frequent primary malignant brain tumour in adults, is characterised by profound yet dynamic hypoxia and nutrient depletion. To sustain survival and proliferation, tumour cells are compelled to acquire metabolic plasticity with the induction of adaptive metabolic programs. Here, we interrogated the pathways necessary to enable processing of nutrients other than glucose. We employed genetic approaches (stable/inducible overexpression, CRISPR/Cas9 knockout), pharmacological interventions with a novel inhibitor of AMP-activated protein kinase (AMPK) in glioblastoma cell culture systems and a proteomic approach to investigate mechanisms of metabolic plasticity. Moreover, a spatially resolved multiomic analysis was employed to correlate the gene expression pattern of PGC-1α with the local metabolic and genetic architecture in human glioblastoma tissue sections. A switch from glucose to alternative nutrients triggered an activation of AMPK, which in turn activated PGC-1α-dependent adaptive programs promoting mitochondrial metabolism. This sensor-effector mechanism was essential for metabolic plasticity with both functional AMPK and PGC-1α necessary for survival and growth of cells under nonglucose nutrient sources. In human glioblastoma tissue specimens, PGC-1α-expression correlated with nonhypoxic tumour niches defining a specific metabolic compartment. Our findings reveal a cell-intrinsic nutrient sensing and switching mechanism. The exposure to alternative fuels triggers a starvation signal that subsequently is passed on via AMPK and PGC-1α to induce adaptive programs necessary for broader spectrum nutrient metabolism. The integration of spatially resolved transcriptomic data confirms the relevance of PGC-1α especially in nonhypoxic tumour regions. Thus, the AMPK-PGC-1α axis is a candidate for therapeutic inhibition in glioblastoma. KEY POINTS/HIGHLIGHTS: AMPK activation induces PGC-1α expression in glioblastoma during nutrient scarcity. PGC-1α enables metabolic plasticity by facilitating metabolism of alternative nutrients in glioblastoma. PGC-1α expression is inversely correlated with hypoxic tumour regions in human glioblastomas.
    Keywords:  AMP‐activated protein kinase; PGC‐1α; PPARGC1A; glioblastoma; hypoxia; metabolic plasticity; tumour microenvironment
    DOI:  https://doi.org/10.1002/ctm2.70030
  11. Nat Commun. 2024 Nov 22. 15(1): 10133
    Mitochondrial heteroplasmy improves risk prediction for myeloid neoplasms.
    Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J Lake, Monkol Lek, Meng Ru, Megan L Grove, Anna Prizment, Corinne E Joshu, Elizabeth A Platz, Eliseo Guallar, Dan E Arking, Lukasz P Gondek.
      Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with higher predicted deleteriousness increase the risk of myeloid neoplasms. Incorporating heteroplasmy in an existing risk score model for individuals with clonal hematopoiesis of indeterminate potential significantly improves sensitivity and better identifies high-risk groups. This suggests heteroplasmy as a clonal expansion marker and potentially as a biomarker for myeloid neoplasms development.
    DOI:  https://doi.org/10.1038/s41467-024-54443-3
  12. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  13. Cancer Metab. 2024 Nov 19. 12(1): 35
    Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
    Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.
       BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
    METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
    RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
    CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.
    Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria
    DOI:  https://doi.org/10.1186/s40170-024-00364-0
  14. Commun Biol. 2024 Nov 21. 7(1): 1551
    Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.
    Christopher S Morrow, Pallas Yao, Carlos A Vergani-Junior, Praju Vikas Anekal, Paula Montero Llopis, Jeffrey W Miller, Bérénice A Benayoun, William B Mair.
      Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as "mito-NAD(P)H age clocks." Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.
    DOI:  https://doi.org/10.1038/s42003-024-07243-w
  15. Cell Calcium. 2024 Nov 16. pii: S0143-4160(24)00129-5. [Epub ahead of print]124 102971
    Electrogenic and non-electrogenic ion antiporters participate in controling membrane potential.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      In a comment to our recent publication, Nicholls question our results and interpretation based on theoretical arguments that reveal a profound misunderstanding of our publication.
    Keywords:  Antiporters; Membrane potential; Mitochondria; Sodium proton exchange
    DOI:  https://doi.org/10.1016/j.ceca.2024.102971
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