bims-mikwok 2022-08-28 papers

Issue of 2022–08–28
four papers selected by
Avinash N. Mukkala, University of Toronto

Redox Biol. 2022 Aug 13. pii: S2213-2317(22)00203-8. [Epub ahead of print]56 102431

LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells.

Amandine Guérin, Claire Angebault, Sandrina Kinet, Chantal Cazevieille, Manuel Rojo, Jérémy Fauconnier, Alain Lacampagne, Arnaud Mourier, Naomi Taylor, Pascal de Santa Barbara, Sandrine Faure.

YAP1 and TAZ are transcriptional co-activator proteins that play fundamental roles in many biological processes, from cell proliferation and cell lineage fate determination to tumorigenesis. We previously demonstrated that Limb Expression 1 (LIX1) regulates YAP1 and TAZ activity and controls digestive mesenchymal progenitor proliferation. However, LIX1 mode of action remains elusive. Here, we found that endogenous LIX1 is localized in mitochondria and is anchored to the outer mitochondrial membrane through S-palmitoylation of cysteine 84, a residue conserved in all LIX1 orthologs. LIX1 downregulation altered the mitochondrial ultrastructure, resulting in a significantly decreased respiration and attenuated production of mitochondrial reactive oxygen species (mtROS). Mechanistically, LIX1 knock-down impaired the stability of the mitochondrial proteins PHB2 and OPA1 that are found in complexes with mitochondrial-specific phospholipids and are required for cristae organization. Supplementation with unsaturated fatty acids counteracted the effects of LIX1 knock-down on mitochondrial morphology and ultrastructure and restored YAP1/TAZ signaling. Collectively, our data demonstrate that LIX1 is a key regulator of cristae organization, modulating mtROS level and subsequently regulating the signaling cascades that control fate commitment of digestive mesenchyme-derived cells.

Keywords: Cell fate; Cristae; Linoleic acid; Mitochondria; Sarcoma; Smooth muscle; YAP1/TAZ; mtROS

DOI: https://doi.org/10.1016/j.redox.2022.102431

Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00304-6. [Epub ahead of print]

Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.

Xiaotong Hong, Joan Isern, Silvia Campanario, Eusebio Perdiguero, Ignacio Ramírez-Pardo, Jessica Segalés, Pablo Hernansanz-Agustín, Andrea Curtabbi, Oleg Deryagin, Angela Pollán, José A González-Reyes, José M Villalba, Marco Sandri, Antonio L Serrano, José A Enríquez, Pura Muñoz-Cánoves.

Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells-due to aging or genetic impairment-deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.

Keywords: Drp1; OXPHOS; aging; metabolism; mitochondria; mitochondrial dynamics; mitophagy; muscle regeneration; muscle stem cells; satellite cells

DOI: https://doi.org/10.1016/j.stem.2022.07.009

Antioxidants (Basel). 2022 Jul 29. pii: 1487. [Epub ahead of print]11(8):

Reverse and Forward Electron Flow-Induced H2O2 Formation Is Decreased in α-Ketoglutarate Dehydrogenase (α-KGDH) Subunit (E2 or E3) Heterozygote Knock Out Animals.

Gergő Horváth, Gergely Sváb, Tímea Komlódi, Dora Ravasz, Gergely Kacsó, Judit Doczi, Christos Chinopoulos, Attila Ambrus, László Tretter.

α-ketoglutarate dehydrogenase complex (KGDHc), or 2-oxoglutarate dehydrogenase complex (OGDHc) is a rate-limiting enzyme in the tricarboxylic acid cycle, that has been identified in neurodegenerative diseases such as in Alzheimer's disease. The aim of the present study was to establish the role of the KGDHc and its subunits in the bioenergetics and reactive oxygen species (ROS) homeostasis of brain mitochondria. To study the bioenergetic profile of KGDHc, genetically modified mouse strains were used having a heterozygous knock out (KO) either in the dihydrolipoyl succinyltransferase (DLST+/-) or in the dihydrolipoyl dehydrogenase (DLD+/-) subunit. Mitochondrial oxygen consumption, hydrogen peroxide (H2O2) production, and expression of antioxidant enzymes were measured in isolated mouse brain mitochondria. Here, we demonstrate that the ADP-stimulated respiration of mitochondria was partially arrested in the transgenic animals when utilizing α-ketoglutarate (α-KG or 2-OG) as a fuel substrate. Succinate and α-glycerophosphate (α-GP), however, did not show this effect. The H2O2 production in mitochondria energized with α-KG was decreased after inhibiting the adenine nucleotide translocase and Complex I (CI) in the transgenic strains compared to the controls. Similarly, the reverse electron transfer (RET)-evoked H2O2 formation supported by succinate or α-GP were inhibited in mitochondria isolated from the transgenic animals. The decrease of RET-evoked ROS production by DLST+/- or DLD+/- KO-s puts the emphasis of the KGDHc in the pathomechanism of ischemia-reperfusion evoked oxidative stress. Supporting this notion, expression of the antioxidant enzyme glutathione peroxidase was also decreased in the KGDHc transgenic animals suggesting the attenuation of ROS-producing characteristics of KGDHc. These findings confirm the contribution of the KGDHc to the mitochondrial ROS production and in the pathomechanism of ischemia-reperfusion injury.

Keywords: DLD; DLST; KGDHc; OGDHc; RET; ROS; antioxidant systems; cellular respiration; ischemia-reperfusion; mitochondria; oxoglutarate dehydrogenase complex; reactive oxygen species; reverse electron transfer; succinate; transgenic animal; α-glycerophosphate; α-ketoglutarate dehydrogenase complex

DOI: https://doi.org/10.3390/antiox11081487

Autophagy. 2022 Aug 26.

LEAP: a novel LC3C-dependent pathway connects autophagy, endocytic trafficking and signaling.

Paula P Coelho, Morag Park.

Macroautophagy/autophagy acts to promote homeostasis and is increasingly understood to selectively target cargo for degradation. The LC3-family of proteins mediate diverse yet distinct cargo recruitment to phagophores. However, what underlies specificity for cargo engagement among LC3 proteins is poorly understood. Using an unbiased protein interaction screen of LC3B and LC3C we uncover a novel LC3C-endocytic-associated-pathway (LEAP) that recruits selective plasma membrane (PM) cargo to phagophores. We show LC3C but not LC3B localizes to peripheral endosomes and engages proteins that traffic between the PM, endosomes and autophagosomes. We establish that endocytic LC3C binds cargo internalized from the PM, including MET receptor tyrosine kinase and TFRC (transferrin receptor), and targets them towards autophagic degradation. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signaling and autophagic degradation with important implications in cancer and other disease states.

Keywords: Atg8-orthologs; LC3C; MET-RTK; autophagy; endocytic trafficking; selective cargo recruitment; signalophagy

DOI: https://doi.org/10.1080/15548627.2022.2117973