bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒08‒21
fifteen papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
  2. Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.
  3. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
  4. SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis.
  5. Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
  6. Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.
  7. ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER-mitochondria contact sites.
  8. Proteasome granule formation is regulated through mitochondrial respiration and kinase signaling.
  9. UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
  10. Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
  11. Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.
  12. Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.
  13. Mitochondrial miRNAs (MitomiRs): Their potential roles in breast and other cancers.
  14. PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.
  15. Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
  1. Cell Metab. 2022 Aug 11. pii: S1550-4131(22)00310-2. [Epub ahead of print]
    The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
    Kaili Xue, Dongmei Wu, Yushuang Wang, Yiheng Zhao, Hongyu Shen, Jingfei Yao, Xun Huang, Xinmeng Li, Zhao Zhou, Zihao Wang, Yifu Qiu.
      Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a "thermoporter" that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.
    Keywords:  UCP1; brown adipose tissue; metabolic dysfunction; mitochondrial calcium uniporter; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.011
  2. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2120157119
    Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.
    Themis Thoudam, Dipanjan Chanda, Ibotombi Singh Sinam, Byung-Gyu Kim, Mi-Jin Kim, Chang Joo Oh, Jung Yi Lee, Min-Ji Kim, Soo Yeun Park, Shin Yup Lee, Min-Kyo Jung, Ji Young Mun, Robert A Harris, Naotada Ishihara, Jae-Han Jeon, In-Kyu Lee.
      Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
    Keywords:  OCR; dynamin-related protein 1; mitochondrial fission; pyruvate dehydrogenase kinase 4; septin 2
    DOI:  https://doi.org/10.1073/pnas.2120157119
  3. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01015-4. [Epub ahead of print]40(7): 111198
    Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
    Mahmud O Abdullah, Run X Zeng, Chelsea L Margerum, David Papadopoli, Cian Monnin, Kaylee B Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J W Rattray, Sheela A Abraham, Eeva-Liisa Eskelinen, David G Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y W Chan.
      The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
    Keywords:  CP: Cell biology; CP: Metabolism; Drp1; Mfn1; Mfn2; Opa1; amino acid sensing; arginine; dynamics; fusion; glutamine; hyperfusion; leucine; mitochondria; stable isotope tracer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111198
  4. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01050-6. [Epub ahead of print]40(7): 111233
    SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis.
    Erica Pranzini, Elisa Pardella, Livio Muccillo, Angela Leo, Ilaria Nesi, Alice Santi, Matteo Parri, Tong Zhang, Alejandro Huerta Uribe, Tiziano Lottini, Lina Sabatino, Anna Caselli, Annarosa Arcangeli, Giovanni Raugei, Vittorio Colantuoni, Paolo Cirri, Paola Chiarugi, Oliver D K Maddocks, Paolo Paoli, Maria Letizia Taddei.
      5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.
    Keywords:  5-FU resistance; CP: Cancer; DNA damage response; Serine metabolism; colorectal cancer; mitochondrial metabolism; nucleotide metabolism; one-carbon metabolism (OCM)
    DOI:  https://doi.org/10.1016/j.celrep.2022.111233
  5. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01010-5. [Epub ahead of print]40(7): 111193
    Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
    Nancy Gudgeon, Haydn Munford, Emma L Bishop, James Hill, Taylor Fulton-Ward, David Bending, Jennie Roberts, Daniel A Tennant, Sarah Dimeloe.
      Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo.
    Keywords:  CP: immunology; CP: metabolism; T cell; metabolism; metabolite; succinate; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111193
  6. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01021-X. [Epub ahead of print]40(7): 111204
    Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.
    Chao Liang, Shan Zhang, David Robinson, Matthew Vander Ploeg, Rebecca Wilson, Jiemin Nah, Dale Taylor, Sheryl Beh, Radiance Lim, Lei Sun, Deborah M Muoio, David A Stroud, Lena Ho.
      Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII), controlling ubiquinol:ubiquinone ratio in ETC, is an attractive node for modulating ETC levels during metabolic stress. Here, we report the discovery of mammalian Co-ordinator of mitochondrial CYTB (COM) complexes that regulate the stepwise CIII biogenesis in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and membrane anchor C16ORF91, facilitates translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN together with COMA subunits form the COMB complex to stabilize nascent CYTB. Finally, UQCC3-containing COMC facilitates CYTB hemylation and association with downstream CIII subunits. Furthermore, when nuclear CIII subunits are limiting, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis and uncover the roles of microproteins in maintaining mitochondrial homeostasis.
    Keywords:  CP: Metabolism; CYTB; SEPs; SMIM4; UQCC1; UQCC2; complex III; electron transport chain; microproteins; nuclear-mitochondrial coordination; smORFs
    DOI:  https://doi.org/10.1016/j.celrep.2022.111204
  7. J Cell Biol. 2022 Sep 05. pii: e202112107. [Epub ahead of print]221(9):
    ORP5 and ORP8 orchestrate lipid droplet biogenesis and maintenance at ER-mitochondria contact sites.
    Valentin Guyard, Vera Filipa Monteiro-Cardoso, Mohyeddine Omrane, Cécile Sauvanet, Audrey Houcine, Claire Boulogne, Kalthoum Ben Mbarek, Nicolas Vitale, Orestis Faklaris, Naima El Khallouki, Abdou Rachid Thiam, Francesca Giordano.
      Lipid droplets (LDs) are the primary organelles of lipid storage, buffering energy fluctuations of the cell. They store neutral lipids in their core that is surrounded by a protein-decorated phospholipid monolayer. LDs arise from the endoplasmic reticulum (ER). The ER protein seipin, localizing at ER-LD junctions, controls LD nucleation and growth. However, how LD biogenesis is spatially and temporally coordinated remains elusive. Here, we show that the lipid transfer proteins ORP5 and ORP8 control LD biogenesis at mitochondria-associated ER membrane (MAM) subdomains, enriched in phosphatidic acid. We found that ORP5/8 regulates seipin recruitment to these MAM-LD contacts, and their loss impairs LD biogenesis. Importantly, the integrity of ER-mitochondria contact sites is crucial for ORP5/8 function in regulating seipin-mediated LD biogenesis. Our study uncovers an unprecedented ORP5/8 role in orchestrating LD biogenesis and maturation at MAMs and brings novel insights into the metabolic crosstalk between mitochondria, ER, and LDs at the membrane contact sites.
    DOI:  https://doi.org/10.1083/jcb.202112107
  8. J Cell Sci. 2022 Aug 17. pii: jcs.259778. [Epub ahead of print]
    Proteasome granule formation is regulated through mitochondrial respiration and kinase signaling.
    Kenrick A Waite, Jeroen Roelofs.
      In yeast, proteasomes are enriched in cell nuclei where they execute important cellular functions. Nutrient-stress can change this localization indicating proteasomes respond to the cell's metabolic state. However, the signals that connect these processes remain poorly understood. Carbon starvation triggers a reversible translocation of proteasomes to cytosolic condensates known as proteasome storage granules (PSGs). Surprisingly, we observed strongly reduced levels of proteasome granules when cells had active cellular respiration prior to starvation. This suggests the mitochondrial activity of cells is a determining factor in the response of proteasomes to carbon starvation. Consistent with this, upon inhibition of mitochondrial function we observed proteasomes relocalize to granules. These links between proteasomes and metabolism involve specific signaling pathways, as we identified a MAP kinase cascade that is critical to the formation of proteasome granules after respiratory growth but not following glycolytic growth. Furthermore, the yeast homolog of AMP kinase, Snf1, is important for proteasome granule formation induced by mitochondrial inhibitors, while dispensable for granule formation following carbon starvation. We propose a model where mitochondrial activity promotes proteasome nuclear localization.
    Keywords:  MAP kinases; Mitochondrial inhibition; Mitochondrial respiration; Proteaphagy; Proteasome; Proteasome storage granules (PSG)
    DOI:  https://doi.org/10.1242/jcs.259778
  9. EMBO Rep. 2022 Aug 18. e54859
    UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
    Jing Zheng, Yu Cao, Jun Yang, Hui Jiang.
      The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knockout also hyperactivates mitophagy. We identify pro-apoptotic BH3-only proteins Noxa, Bik, and Bnip3 as novel UBXD8 substrates and determine that UBXD8 inhibits apoptosis via degrading Noxa and restrains mitophagy via degrading Bnip3. Collectively, our characterizations reveal UBXD8 as the major mitochondrial adaptor of VCP and unveil its role in apoptosis and mitophagy regulation.
    Keywords:  UBXD8; VCP; apoptosis; mitochondria-associated degradation; mitophagy
    DOI:  https://doi.org/10.15252/embr.202254859
  10. PLoS Comput Biol. 2022 Aug 19. 18(8): e1010413
    Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
    Ximena G Arceo, Elena F Koslover, Brian M Zid, Aidan I Brown.
      For many nuclear-encoded mitochondrial genes, mRNA localizes to the mitochondrial surface co-translationally, aided by the association of a mitochondrial targeting sequence (MTS) on the nascent peptide with the mitochondrial import complex. For a subset of these co-translationally localized mRNAs, their localization is dependent on the metabolic state of the cell, while others are constitutively localized. To explore the differences between these two mRNA types we developed a stochastic, quantitative model for MTS-mediated mRNA localization to mitochondria in yeast cells. This model includes translation, applying gene-specific kinetics derived from experimental data; and diffusion in the cytosol. Even though both mRNA types are co-translationally localized we found that the steady state number, or density, of ribosomes along an mRNA was insufficient to differentiate the two mRNA types. Instead, conditionally-localized mRNAs have faster translation kinetics which modulate localization in combination with changes to diffusive search kinetics across metabolic states. Our model also suggests that the MTS requires a maturation time to become competent to bind mitochondria. Our work indicates that yeast cells can regulate mRNA localization to mitochondria by controlling mitochondrial volume fraction (influencing diffusive search times) and gene translation kinetics (adjusting mRNA binding competence) without the need for mRNA-specific binding proteins. These results shed light on both global and gene-specific mechanisms that enable cells to alter mRNA localization in response to changing metabolic conditions.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010413
  11. Sci Transl Med. 2022 Aug 17. 14(658): eabk1051
    Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.
    Ashwin V Venkataraman, Ayla Mansur, Gaia Rizzo, Courtney Bishop, Yvonne Lewis, Ece Kocagoncu, Anne Lingford-Hughes, Mickael Huiban, Jan Passchier, James B Rowe, Hideo Tsukada, David J Brooks, Laurent Martarello, Robert A Comley, Laigao Chen, Adam J Schwarz, Richard Hargreaves, Roger N Gunn, Eugenii A Rabiner, Paul M Matthews.
      Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.
    DOI:  https://doi.org/10.1126/scitranslmed.abk1051
  12. Nucleic Acids Res. 2022 Aug 18. pii: gkac690. [Epub ahead of print]
    Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.
    Nguyen Thi Kim Oanh, Ho-Soo Lee, Yong-Hyun Kim, Sunwoo Min, Yeon-Ji Park, June Heo, Yong-Yea Park, Won-Chung Lim, Hyeseong Cho.
      Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.
    DOI:  https://doi.org/10.1093/nar/gkac690
  13. Mitochondrion. 2022 Aug 10. pii: S1567-7249(22)00071-X. [Epub ahead of print]66 74-81
    Mitochondrial miRNAs (MitomiRs): Their potential roles in breast and other cancers.
    Elif Erturk, Omer Enes Onur, Oguzhan Akgun, Gonca Tuna, Yaren Yildiz, Ferda Ari.
      Breast cancer is the most common cancer in women worldwide. MicroRNAs (miRNAs) are non-coding RNAs that are involved in the post-transcriptional regulation of gene expression. Although miRNAs mainly act in the cytoplasm, they can be found in the mitochondrial compartment of the cell. These miRNAs called "MitomiR", they can change mitochondrial functions by regulating proteins at the mitochondrial level and cause cancer. In this review, we have aimed to explain miRNA biogenesis, transport pathways to mitochondria, and summarize mitomiRs that have been shown to play an important role in mitochondrial function, especially in the initiation and progression of breast cancer.
    Keywords:  Breast Cancer; Mitochondria; MitomiRs; miRNAs
    DOI:  https://doi.org/10.1016/j.mito.2022.08.002
  14. Biochem Biophys Res Commun. 2022 Aug 05. pii: S0006-291X(22)01109-3. [Epub ahead of print]625 167-173
    PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.
    Natsumi Miyazaki, Reika Shiratori, Taichi Oshima, Zhiheng Zhang, Robert Valencia, Joshua Kranrod, Liye Fang, John M Seubert, Kousei Ito, Shigeki Aoki.
      Cancer cells rely on glycolysis to generate ATP for survival. However, inhibiting glycolysis is insufficient for the eradication of cancer cells because glycolysis-suppressed cells undergo metabolic reprogramming toward mitochondrial oxidative phosphorylation. We previously described that upon glycolytic suppression in pancreatic cancer cells, intracellular glycometabolism is shifted toward mitochondrial oxidative phosphorylation in an autophagy-dependent manner for cellular survival. Here, we hypothesized that mitophagy, which selectively degrades mitochondria via autophagy, is involved in mitochondrial activation under metabolic reprogramming. We revealed that glycolytic suppression notably increased mitochondrial membrane potential and mitophagy in a pancreatic cancer cell model (PANC-1). PTEN-induced kinase 1 (PINK1), a ubiquitin kinase that regulates mitophagy in healthy cells, regulated mitochondrial activation through mitophagy by glycolytic suppression. However, Parkin, a ubiquitin ligase regulated by PINK1 in healthy cells to induce mitophagy, was not involved in the PINK1-dependent mitophagy of the cancer glycometabolism. These results imply that cancer cells and healthy cells have different regulatory pieces of machinery for mitophagy, and inhibition of cancer-specific mechanisms may be a potential strategy for cancer therapy targeting metabolic reprogramming.
    Keywords:  Glycometabolism; Mitophagy; PINK1; Pancreatic cancer; Parkin
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.004
  15. PLoS One. 2022 ;17(8): e0273080
    Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
    Yu Hui Kang, Sarah A Tucker, Silvia F Quevedo, Aslihan Inal, Joshua R Korzenik, Marcia C Haigis.
      Ulcerative colitis (UC) is a complex, multifactorial disease driven by a dysregulated immune response against host commensal microbes. Despite rapid advances in our understanding of host genomics and transcriptomics, the metabolic changes in UC remain poorly understood. We thus sought to investigate distinguishing metabolic features of the UC colon (14 controls and 19 patients). Metabolomics analyses revealed inflammation state as the primary driver of metabolic variation rather than diagnosis, with multiple metabolites differentially regulated between inflamed and uninflamed tissues. Specifically, inflamed tissues were characterized by reduced levels of nicotinamide adenine dinucleotide (NAD+) and enhanced levels of nicotinamide (NAM) and adenosine diphosphate ribose (ADPr). The NAD+/NAM ratio, which was reduced in inflamed patients, served as an effective classifier for inflammation in UC. Mitochondria were also structurally altered in UC, with UC patient colonocytes displaying reduced mitochondrial density and number. Together, these findings suggest a link between mitochondrial dysfunction, inflammation, and NAD+ metabolism in UC.
    DOI:  https://doi.org/10.1371/journal.pone.0273080
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