bims-midtic 2023-10-15 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023‒10‒15
27 papers selected by
Omkar Joshi, Turku Bioscience

Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.
Extracellular release in the quality control of the mammalian mitochondria.
Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
Brain mitochondria in behavior: more than a powerhouse.
Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration.
PLAAT1 expression triggers fragmentation of mitochondria in an enzyme activity-dependent manner.
C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes.
Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.
Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.
Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.
FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.
Characterization of differential distribution patterns between mitofusin isoforms and their interaction in developing skeletal muscles of rat.
BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.
Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.
PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.
Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.
Plasmodium falciparum OPA3-like protein (PfOPA3) is essential for maintenance of mitochondrial homeostasis and parasite proliferation.
Increased Ca2 + transport across the mitochondria-associated membranes by Mfn2 inhibiting endoplasmic reticulum stress in ischemia/reperfusion kidney injury.
Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.
Autophagy protects mitochondrial health in heart failure.
Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.
Apoptotic stress causes mtDNA release during senescence and drives the SASP.
Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.
Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis.
Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.

Development. 2023 Oct 12. pii: dev.201930. [Epub ahead of print]

Calcium signals tune AMPK activity and mitochondrial homeostasis in dendrites of developing neurons.

Akane Hatsuda, Junko Kurisu, Kazuto Fujishima, Ayano Kawaguchi, Nobuhiko Ohno, Mineko Kengaku.

  Dendritic outgrowth in immature neurons is enhanced by neuronal activity and is considered one of the mechanisms of neural circuit optimization. It is known that calcium signals affect transcriptional regulation and cytoskeletal remodeling necessary for dendritic outgrowth. Here we demonstrate that activity-dependent calcium signaling also controls mitochondrial homeostasis via AMP-activated protein kinase (AMPK) in growing dendrites of differentiating hippocampal neurons. We found that the inhibition of neuronal activity induces dendritic hypotrophy with abnormally elongated mitochondria. In growing dendrites, AMPK is activated by neuronal activity and dynamically oscillates in synchrony with calcium spikes, and this AMPK oscillation is inhibited by CaMKK2 knockdown. AMPK activation leads to phosphorylation of MFF and ULK1, which initiate mitochondrial fission and mitophagy, respectively. Dendritic mitochondria in AMPK-depleted neurons exhibit impaired fission and mitophagy and display multiple signs of dysfunction. Genetic inhibition of fission leads to dendritic hypoplasia reminiscent of AMPK deficient neurons. Thus, AMPK activity is finely tuned by the calcium-CaMKK2 pathway and regulates mitochondrial homeostasis by facilitating removal of damaged components of mitochondria in growing neurons during normal brain development.

Keywords:  AMPK; Dendritogenesis; Hippocampal neurons; Mitochondria; Neuronal activity

DOI:  https://doi.org/10.1242/dev.201930
J Biomed Sci. 2023 Oct 08. 30(1): 85

Extracellular release in the quality control of the mammalian mitochondria.

Kuei-Hsiang Pan, Hung Chang, Wei Yuan Yang.

  Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.

Keywords:  Autophagy; Extracellular vesicles; Mitochondria; Mitophagy; Organelle quality control

DOI:  https://doi.org/10.1186/s12929-023-00979-3
Mol Cell Biol. 2023 ;43(10): 531-546

Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.

Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner.

  During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.

Keywords:  fission; fusion; histone lactylation; inflammation resolution; macrophages; mitochondrial metabolism

DOI:  https://doi.org/10.1080/10985549.2023.2253131
EMBO Rep. 2023 Oct 11. e57228

Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.

Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.

  Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines

DOI:  https://doi.org/10.15252/embr.202357228
Trends Endocrinol Metab. 2023 Oct 05. pii: S1043-2760(23)00197-2. [Epub ahead of print]

Brain mitochondria in behavior: more than a powerhouse.

Alexia Crockett, Fiona Hollis.

  Rosenberg and colleagues developed a miniaturized assay of mitochondrial content and energy transformation capacity that allowed them to assess mitochondrial features and activities across the brain in male mice. Their findings provide a comprehensive brain-wide map of mitochondrial associations with stress-induced behaviors and highlight mitochondria as dynamic, spatially-organized organelles.

Keywords:  behavior; brain bioenergetics; mitochondria; stress

DOI:  https://doi.org/10.1016/j.tem.2023.09.008
J Transl Med. 2023 Oct 10. 21(1): 711

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration.

Wencan Ke, Bingjin Wang, Zhiwei Liao, Yu Song, Gaocai Li, Liang Ma, Kun Wang, Shuai Li, Wenbin Hua, Cao Yang.

  BACKGROUND: Extracellular matrix stiffness is emerging as a crucial mechanical cue that drives the progression of various diseases, such as cancer, fibrosis, and inflammation. The matrix stiffness of the nucleus pulposus (NP) tissues increase gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In addition, mitochondrial dynamics play a key role in various cellular functions. An in-depth investigation of the pathogenesis of IDD can provide new insights for the development of effective therapies. In this study, we aim to investigate the effects of matrix stiffness on mitochondrial dynamics in IDD.METHODS: To build the gradient stiffness model, NP cells were cultured on polystyrene plates with different stiffness. Western blot analysis, and immunofluorescence staining were used to detect the expression of mitochondrial dynamics-related proteins. Flow cytometry was used to detect the mitochondrial membrane potential and intracellular Ca2+ levels. Apoptosis related proteins, ROS level, and TUNEL staining were performed to assess the effect of substrate stiffness on NP cells.
RESULTS: Stiff substrate increased phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 by activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which promoted mitochondrial fission and apoptosis in NP cells. Furthermore, Piezo1 activation was involved in the regulation of the post-translational modifications of Drp1 and mitochondrial fission caused by matrix stiffness. Inhibition of Piezo1 and ERK1/2 can effectively reduce stiffness-induced ROS elevation and apoptosis in NP cells.
CONCLUSIONS: Our results revealed that stiff substrate causes Piezo1 activation and Ca2+ influx, results in ERK1/2 activation and phosphorylation of Drp1 at S616, and finally leads to mitochondrial fission and apoptosis in NP cells. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for treating IDD.

Keywords:  Intervertebral disc degeneration; Matrix stiffness; Mechanotransduction; Mitochondrial fission; Nucleus pulposus; Piezo1

DOI:  https://doi.org/10.1186/s12967-023-04590-w
J Biochem. 2023 Oct 11. pii: mvad079. [Epub ahead of print]

PLAAT1 expression triggers fragmentation of mitochondria in an enzyme activity-dependent manner.

Mohammad Mamun Sikder, Toru Uyama, Sumire Sasaki, Katsuhisa Kawai, Nobukazu Araki, Natsuo Ueda.

  The phospholipase A and acyltransferase (PLAAT) family is a protein family consisting of five members (PLAAT1-5), which acts as phospholipid-metabolizing enzymes with phospholipase A1/A2 and N-acyltransferase activities. Since we previously reported that the overexpression of PLAAT3 in mammalian cells causes the specific disappearance of peroxisomes, in the present study we examined a possible effect of PLAAT1 on organelles. We prepared HEK293 cells expressing mouse PLAAT1 in a doxycycline-dependent manner and found that the overexpression of PLAAT1 resulted in the transformation of mitochondria from the original long rod shape to a round shape, as well as their fragmentation. In contrast, the overexpression of a catalytically inactive point mutant of PLAAT1 did not generate any morphological change in mitochondria, suggesting the involvement of catalytic activity. PLAAT1 expression also caused the reduction of peroxisomes, while the levels of the marker proteins for ER, Golgi apparatus, and lysosomes were almost unchanged. In PLAAT1-expressing cells, the level of dynamin-related protein 1 responsible for mitochondrial fission was increased, whereas those of optic atrophy 1 and mitofusin 2, both of which are responsible for mitochondrial fusion, were reduced. These results suggest a novel role of PLAAT1 in the regulation of mitochondrial biogenesis.

Keywords:  PLAAT; mitochondrion; organelle; peroxisome; phospholipase A2

DOI:  https://doi.org/10.1093/jb/mvad079
BMB Rep. 2023 Oct 11. pii: 5993. [Epub ahead of print]

C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes.

Suyeon Jin, Chan Joo Lee, Gibbeum Lim, Sungha Park, Sang-Hak Lee, Ji Hyung Chung, Jaewon Oh, Seok-Min Kang.

C-reactive protein (CRP) is an inflammatory marker and risk factor for atherosclerosis and cardiovascular diseases. However, the mechanism through which CRP induces myocardial damage remains unclear. This study aimed to determine how CRP damages cardiomyocytes via the change of mitochondrial dynamics and whether survivin, an anti-apoptotic protein, exerts a cardioprotective effect in this process. We treated H9c2 cardiomyocytes with CRP and found increased intracellular ROS production and shortened mitochondrial length. CRP treatment phosphorylated ERK1/2 and promoted increased expression, phosphorylation, and translocation of DRP1, a mitochondrial fission-related protein, from the cytoplasm to the mitochondria. The expression of mitophagy proteins PINK1 and PARK2 was also increased by CRP. YAP, a transcriptional regulator of PINK1 and PARK2, was also increased by CRP. Knockdown of YAP prevented CRP-induced increases in DRP1, PINK1, and PARK2. Furthermore, CRP-induced changes in the expression of DRP1 and increases in YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition, suggesting that ERK1/2 signaling is involved in CRP-induced mitochondrial fission. We treated H9c2 cardiomyocytes with a recombinant TAT-survivin protein before CRP treatment, which reduced CRP-induced ROS accumulation and reduced mitochondrial fission. CRP-induced activation of ERK1/2 and increases in the expression and activity of YAP and its downstream mitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRPinduced cardiomyocyte damage and that the ERK1/2-YAP axis is involved in this process, and identifies that survivin alters these mechanisms to prevent CRP-induced mitochondrial damage.
Brain. 2023 Oct 07. pii: awad347. [Epub ahead of print]

Homozygous MFN2 variants causing severe antenatal encephalopathy with clumped mitochondria.

Arnaud Chevrollier, Adeline Alice Bonnard, Lyse Ruaud, Naïg Gueguen, Laurence Perrin, Valérie Desquiret-Dumas, Fabien Guimiot, Pierre-Hadrien Becker, Jonathan Levy, Pascal Reynier, Pauline Gaignard.

  Pathogenic variants in MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the central nervous system. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole Genome Analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane (MOM) that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the MOM. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.

Keywords:  early onset; mitochondrial dynamics; mitochondrial fusion; neurological disorders

DOI:  https://doi.org/10.1093/brain/awad347
Cell Death Dis. 2023 Oct 10. 14(10): 664

Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

Sumati Hasani, Lyndsay E A Young, Warren Van Nort, Moumita Banerjee, Dylan R Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C Sun, Matthew S Gentry, Hiromi Sesaki, Tianyan Gao.

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apcf/f/Villin-CreERT2 models, we show that glycogen levels are elevated in tumor organoids upon genetic deletion of Drp1. Similarly, increased GYS1 expression and glycogen accumulation are detected in xenograft tumors derived from Drp1 knockdown colon cancer cells. Functionally, increased glycogen storage provides survival advantage to Drp1 knockdown cells. Co-targeting glycogen phosphorylase-mediated glycogenolysis sensitizes Drp1 knockdown cells to chemotherapy drug treatment. Taken together, our results suggest that Drp1-loss activates glucose uptake and glycogenesis as compensative metabolic pathways to promote cell survival. Combined inhibition of glycogen metabolism may enhance the efficacy of chemotherapeutic agents for colon cancer treatment.

DOI: https://doi.org/10.1038/s41419-023-06202-3
Cancer Cell. 2023 Oct 09. pii: S1535-6108(23)00319-7. [Epub ahead of print]41(10): 1788-1802.e10

Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution.

Hongyi Zhang, Xuexin Yu, Jianfeng Ye, Huiyu Li, Jing Hu, Yuhao Tan, Yan Fang, Esra Akbay, Fulong Yu, Chen Weng, Vijay G Sankaran, Robert M Bachoo, Elizabeth Maher, John Minna, Anli Zhang, Bo Li.

  Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.

Keywords:  Mitochondrial Transfer; Statistical Deconvolution; T cell dysfunction; Tumor-Immune Interaction; mtDNA sequencing.; single cell genomics

DOI:  https://doi.org/10.1016/j.ccell.2023.09.003
Nat Commun. 2023 10 10. 14(1): 6344

FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.

Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.

Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.

DOI: https://doi.org/10.1038/s41467-023-41988-y
Elife. 2023 Oct 12. pii: RP88084. [Epub ahead of print]12

Structural rather than catalytic role for mitochondrial respiratory chain supercomplexes.

Michele Brischigliaro, Alfredo Cabrera-Orefice, Susanne Arnold, Carlo Viscomi, Massimo Zeviani, Erika Fernández-Vizarra.

  Mammalian mitochondrial respiratory chain (MRC) complexes are able to associate into quaternary structures named supercomplexes (SCs), which normally coexist with non-bound individual complexes. The functional significance of SCs has not been fully clarified and the debate has been centered on whether or not they confer catalytic advantages compared with the non-bound individual complexes. Mitochondrial respiratory chain organization does not seem to be conserved in all organisms. In fact, and differently from mammalian species, mitochondria from Drosophila melanogaster tissues are characterized by low amounts of SCs, despite the high metabolic demands and MRC activity shown by these mitochondria. Here, we show that attenuating the biogenesis of individual respiratory chain complexes was accompanied by increased formation of stable SCs, which are missing in Drosophila melanogaster in physiological conditions. This phenomenon was not accompanied by an increase in mitochondrial respiratory activity. Therefore, we conclude that SC formation is necessary to stabilize the complexes in suboptimal biogenesis conditions, but not for the enhancement of respiratory chain catalysis.

Keywords:  D. melanogaster; Drosophila; Mitochondria; OXPHOS; biochemistry; chemical biology; supercomplexes

DOI:  https://doi.org/10.7554/eLife.88084
J Cell Biochem. 2023 Oct 10.

Characterization of differential distribution patterns between mitofusin isoforms and their interaction in developing skeletal muscles of rat.

Unmod Senapati, Sunil Pani, Subhasmita Rout, Bijayashree Sahu, Punyadhara Pani, Gourabamani Swalsingh, Benudhara Pati, Naresh C Bal.

  Skeletal muscle during postnatal development undergoes several structural and biochemical modifications. It is proposed that these changes are closely intertwined with the increase in load-bearing capacity of the muscle (i.e., myofibrils) and molecular machinery to support the energy demand (i.e., mitochondria). Concomitant establishment of the sarcoplasmic reticulum (SR) and mitochondrial network seems to be a major developmental adjustment of skeletal muscle leading to adult phenotype. Here, we have studied oxidativeness, vascularization, and the changes in mitofusins (Mfn) 1-Mfn 2 expression and interaction in the due course of muscle development. Toward this, we used a series of histochemical techniques to compare neonatal and adult limb muscles (Gastrocnemius and Quadriceps) of Wistar rat (Rattus norvegicus). Additionally, we probed the proximity between Mfn 1 and Mfn 2 using a highly sensitive antibody-based proximity ligation assay indicating the change in mitochondrial fusion pattern or mitochondria-SR interaction. The results show that neonatal fibers bear a uniform distribution of mitochondria while a differential pattern of distribution is seen in adults. The distribution of the blood vessels is also quite distinct in adult muscles with a well-formed capillary network but in neonates, only central blood vessels are seen. Interestingly, our Mfn 1-Mfn 2 interaction data show that this interaction is uniformly distributed throughout the neonatal fibers, while it becomes peripherally localized in fibers of adult muscles. This peripheralization of Mfn 1-Mfn 2 interaction must be an important event of muscle development and might be critical to cater to the metabolic needs of adult muscle.

Keywords:  development; mitochondria; mitofusins; neonate; protein-protein interaction; skeletal muscle

DOI:  https://doi.org/10.1002/jcb.30489
Nucleic Acids Res. 2023 Oct 12. pii: gkad842. [Epub ahead of print]

BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.

Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, Antoni Barrientos.

The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.

DOI: https://doi.org/10.1093/nar/gkad842
J Biomed Sci. 2023 Oct 12. 30(1): 86

Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis.

Lei Liu, Yanjun Li, Guo Chen, Quan Chen.

  Mitochondrial mass and quality are tightly regulated by two essential and opposing mechanisms, mitochondrial biogenesis (mitobiogenesis) and mitophagy, in response to cellular energy needs and other cellular and environmental cues. Great strides have been made to uncover key regulators of these complex processes. Emerging evidence has shown that there exists a tight coordination between mitophagy and mitobiogenesis, and their defects may cause many human diseases. In this review, we will first summarize the recent advances made in the discovery of molecular regulations of mitobiogenesis and mitophagy and then focus on the mechanism and signaling pathways involved in the simultaneous regulation of mitobiogenesis and mitophagy in the response of tissue or cultured cells to energy needs, stress, or pathophysiological conditions. Further studies of the crosstalk of these two opposing processes at the molecular level will provide a better understanding of how the cell maintains optimal cellular fitness and function under physiological and pathophysiological conditions, which holds promise for fighting aging and aging-related diseases.

Keywords:  Aging; Aging-related diseases; Mitochondrial biogenesis; Mitochondrial quality; Mitophagy; Mitophagy receptors

DOI:  https://doi.org/10.1186/s12929-023-00975-7
Nat Commun. 2023 Oct 13. 14(1): 6431

PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy.

Natalie M Niemi, Lia R Serrano, Laura K Muehlbauer, Catherine E Balnis, Lianjie Wei, Andrew J Smith, Keri-Lyn Kozul, Merima Forny, Olivia M Connor, Edrees H Rashan, Evgenia Shishkova, Kathryn L Schueler, Mark P Keller, Alan D Attie, Jonathan R Friedman, Julia K Pagan, Joshua J Coon, David J Pagliarini.

PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.

DOI: https://doi.org/10.1038/s41467-023-42069-w
Aging Cell. 2023 Oct 13. e14003

Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.

Xi Chen, Zhizhen Wang, Peng Zheng, Anjila Dongol, Yuanyi Xie, Xing Ge, Mingxuan Zheng, Xuemei Dang, Zehra Boz Seyhan, Nathan Nagaratnam, Yinghua Yu, Xu-Feng Huang.

  The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.

Keywords:  accelerated aging; antipsychotics; cognition; health span; lifespan; mitophagy; mitophagy inducer; olanzapine

DOI:  https://doi.org/10.1111/acel.14003
FASEB J. 2023 Nov;37(11): e23235

Plasmodium falciparum OPA3-like protein (PfOPA3) is essential for maintenance of mitochondrial homeostasis and parasite proliferation.

Monika Narwal, Shilpi Jain, Sumit Rathore, Asif Mohmmed.

  Metabolic pathways and proteins responsible for maintaining mitochondrial dynamics and homeostasis in the Plasmodium parasite, the causative agent of malaria, remain to be elucidated. Here, we identified and functionally characterized a novel OPA3-like domain-containing protein in P. falciparum (PfOPA3). We show that PfOPA3 is expressed in the intraerythrocytic stages of the parasite and localizes to the mitochondria. Inducible knock-down of PfOPA3 using GlmS ribozyme hindered the normal intraerythrocytic cycle of the parasites; specifically, PfOPA3-iKD disrupted parasite development as well as parasite division and segregation at schizont stages, which resulted in a drastic reduction in the number of merozoites progenies. Parasites lacking PfOPA3 show severe defects in the development of functional mitochondria; the mitochondria showed reduced activity of mtETC but not ATP synthesis, as evidenced by reduced activity of complex III of the mtETC, and increased sensitivity for drugs targeting DHODH as well as complex III, but not to the drugs targeting complex V. Further, PfOPA3 downregulation leads to reduction in the level of mitochondrial proton transport uncoupling protein (PfUCP) to compensate reduced activity of complex III and maintain proton efflux across the inner membrane. The reduced activity of DHODH, which is responsible for pyrimidine biosynthesis required for nuclear DNA synthesis, resulted in a significant reduction in parasite nuclear division and generation of progeny. In conclusion, we show that PfOPA3 is essential for the functioning of mtETC and homeostasis required for the development of functional mitochondria as well as for parasite segregation, and thus PfOPA3 is crucial for parasite survival during blood stages.

Keywords:   Plasmodium ; OPA3; malaria; mitochondrial homeostasis; mtETC; schizogony

DOI:  https://doi.org/10.1096/fj.202201386RR
Sci Rep. 2023 Oct 12. 13(1): 17257

Increased Ca2 + transport across the mitochondria-associated membranes by Mfn2 inhibiting endoplasmic reticulum stress in ischemia/reperfusion kidney injury.

Shun Wang, Xiaohong Sang, Suhua Li, Wenjun Yang, Shihan Wang, Haixia Chen, Chen Lu.

Renal ischemia/reperfusion (I/R) injury, which leads to acute kidney injury (AKI), is a major cause of morbidity and mortality in a variety of clinical situations. This study aimed to investigate the protective role of Mfn2 during renal I/R injury. Overexpression of Mfn2 in NRK-52E rat renal tubular epithelial cells and rats, then we constructed hypoxia reoxygenation (H/R) cells and I/R rat model. Apoptosis, ROS, ATP, Ca2+ levels in cells and rats, as well as renal tissue and functional injury in rats were detected respectively. Endoplasmic reticulum (ER) stress was further examined in cells and rats. The morphological changes of mitochondria-associated ER membranes (MAMs) were also detected. Mfn2 expression is reduced in H/R-treated NRK-52E cells and renal tissue of I/R rats. At the cellular level, overexpression of Mfn2 promoted cell proliferation, inhibited cell apoptosis, attenuated mitochondrial damage and Ca2+ overload, and ER stress. In addition, Mfn2 also restored the MAMs structure. In vivo experiments found that overexpression of Mfn2 could improve renal function and alleviate tissue injury. Concomitant with elevated Mfn2 expression in the kidney, reduced renal cell apoptosis, restored mitochondrial function, and reduced calcium overload. Finally, ER stress in rat kidney tissue was alleviated after overexpression of Mfn2. These results reveal that Mfn2 contributes to ER stress, mitochondrial function, and cell death in I/R injury, which provides a novel therapeutic target for AKI.

DOI: https://doi.org/10.1038/s41598-023-44538-0
Cancer Lett. 2023 Oct 05. pii: S0304-3835(23)00376-2. [Epub ahead of print] 216425

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

Yan Zhou, Yizhen Guo, Maoxin Ran, Wenying Shan, Carlotta Granchi, Elisa Giovannetti, Filippo Minutolo, Godefridus J Peters, Kin Yip Tam.

  Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.

Keywords:  Anticancer; Combination treatment; Non-small cell lung cancer; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2023.216425
Heart Fail Rev. 2023 Oct 12.

Autophagy protects mitochondrial health in heart failure.

Yating Tang, Wenlong Xu, Yu Liu, Jiajun Zhou, Kai Cui, Yanmei Chen.

  The progression of heart failure is reported to be strongly associated with homeostatic imbalance, such as mitochondrial dysfunction and abnormal autophagy, in the cardiomyocytes. Mitochondrial dysfunction triggers autophagic and cardiac dysfunction. In turn, abnormal autophagy impairs mitochondrial function and leads to apoptosis or autophagic cell death under certain circumstances. These events often occur concomitantly, forming a vicious cycle that exacerbates heart failure. However, the role of the crosstalk between mitochondrial dysfunction and abnormal autophagy in the development of heart failure remains obscure and the underlying mechanisms are mainly elusive. The potential role of the link between mitochondrial dysfunction and abnormal autophagy in heart failure progression has recently garnered attention. This review summarized recent advances of the interactions between mitochondria and autophagy during the development of heart failure.

Keywords:  Autophagy; Heart failure; Mitochondria health; Mitochondria-targeted therapeutics; Mitochondrial quality control

DOI:  https://doi.org/10.1007/s10741-023-10354-x
Nat Commun. 2023 Oct 10. 14(1): 6328

Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice.

Tomas Venit, Oscar Sapkota, Wael Said Abdrabou, Palanikumar Loganathan, Renu Pasricha, Syed Raza Mahmood, Nadine Hosny El Said, Shimaa Sherif, Sneha Thomas, Salah Abdelrazig, Shady Amin, Davide Bedognetti, Youssef Idaghdour, Mazin Magzoub, Piergiorgio Percipalle.

Metabolic reprogramming is one of the hallmarks of tumorigenesis. Here, we show that nuclear myosin 1 (NM1) serves as a key regulator of cellular metabolism. NM1 directly affects mitochondrial oxidative phosphorylation (OXPHOS) by regulating mitochondrial transcription factors TFAM and PGC1α, and its deletion leads to underdeveloped mitochondria inner cristae and mitochondrial redistribution within the cell. These changes are associated with reduced OXPHOS gene expression, decreased mitochondrial DNA copy number, and deregulated mitochondrial dynamics, which lead to metabolic reprogramming of NM1 KO cells from OXPHOS to aerobic glycolysis.This, in turn, is associated with a metabolomic profile typical for cancer cells, namely increased amino acid-, fatty acid-, and sugar metabolism, and increased glucose uptake, lactate production, and intracellular acidity. NM1 KO cells form solid tumors in a mouse model, suggesting that the metabolic switch towards aerobic glycolysis provides a sufficient carcinogenic signal. We suggest that NM1 plays a role as a tumor suppressor and that NM1 depletion may contribute to the Warburg effect at the onset of tumorigenesis.

DOI: https://doi.org/10.1038/s41467-023-42093-w
Nature. 2023 Oct 11.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

DOI: https://doi.org/10.1038/s41586-023-06621-4
Eur J Pharmacol. 2023 Oct 06. pii: S0014-2999(23)00597-6. [Epub ahead of print] 176085

Low-dose atorvastatin protects skeletal muscle mitochondria in high-fat diet-fed mice with mitochondrial autophagy inhibition and fusion enhancement.

Peng Zheng, Qian Zhang, Wenjing Ma, Ran Hu, Yilu Gu, Zhiping Bian, Di Yang, Xiangjian Chen, Hengfang Wu.

  Despite the great clinical benefits of statins in cardiovascular diseases, their widespread use may lead to adverse muscle reactions associated with mitochondrial dysfunction. Some studies have demonstrated that statins provide substantial improvement to skeletal muscle health in mice. Our previous study found that oral treatment with atorvastatin (Ator, 3 mg/kg) protected myocardial mitochondria in high-fat diet (HFD)-fed mice. Therefore, this study aimed to explore the influence of low-dose Ator (3 mg/kg) on mitochondria in skeletal muscle under cholesterol overload. Male C57BL/6J mice were fed a HFD for 18 weeks and orally administered Ator (3 mg/kg) during the last 12 weeks. Ator treatment had no effects on elevated serum cholesterol and glucose levels in HFD-fed mice. Serum creatine kinase levels and the cross-sectional area of muscle cells were not affected by HFD feeding or Ator treatment. Increased expression of PINK1-LC3 II (activated mitophagy), MFN2 (fusion), and PGC-1α (biogenesis) proteins was induced in the skeletal muscles of HFD-fed mice. Treatment with Ator inhibited PINK1 and LC3 II protein expression, but further promoted MFN1, MFN2, and OPA1 expression. The impairments in mitochondrial quality and morphology in HFD-fed mice was attenuated by treatment with Ator. Furthermore, Ator treatment enhanced glucose oxidation capacity and restored ATP production in the skeletal muscles of HFD-fed mice. The study reveals that low-dose Ator has a protective effect on muscle mitochondria in mice, likely through inhibiting mitophagy and enhancing mitochondrial fusion. This suggests that skeletal muscle mitochondria may be one of low-dose Ator-mediated protective targets.

Keywords:  Atorvastatin; High cholesterol; High-fat diet; Mitochondria; Mitochondrial quality-control network; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ejphar.2023.176085
Cancer Gene Ther. 2023 Oct 11.

Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis.

Chi-Yang Tseng, Yu-Hsuan Fu, Da-Liang Ou, Jeng-Wei Lu, Hsin-An Hou, Liang-In Lin.

Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.

DOI: https://doi.org/10.1038/s41417-023-00675-2
bioRxiv. 2023 Sep 29. pii: 2023.09.29.559526. [Epub ahead of print]

Mitochondrial regulator PGC-1a in neuronal metabolism and brain aging.

Dylan C Souder, Eric R McGregor, Timothy W Rhoads, Josef P Clark, Tiaira J Porter, Kevin Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.

The brain is a high energy tissue, and the cell types of which it is comprised are distinct in function and in metabolic requirements. The transcriptional co-activator PGC-1a is a master regulator of mitochondrial function and is highly expressed in the brain; however, its cell-type specific role in regulating metabolism has not been well established. Here, we show that PGC-1a is responsive to aging and that expression of the neuron specific PGC-1a isoform allows for specialization in metabolic adaptation. Transcriptional profiles of the cortex from male mice show an impact of age on immune, inflammatory, and neuronal functional pathways and a highly integrated metabolic response that is associated with decreased expression of PGC-1a. Proteomic analysis confirms age-related changes in metabolism and further shows changes in ribosomal and RNA splicing pathways. We show that neurons express a specialized PGC-1a isoform that becomes active during differentiation from stem cells and is further induced during the maturation of isolated neurons. Neuronal but not astrocyte PGC-1a responds robustly to inhibition of the growth sensitive kinase GSK3b, where the brain specific promoter driven dominant isoform is repressed. The GSK3b inhibitor lithium broadly reprograms metabolism and growth signaling, including significantly lower expression of mitochondrial and ribosomal pathway genes and suppression of growth signaling, which are linked to changes in mitochondrial function and neuronal outgrowth. In vivo, lithium treatment significantly changes the expression of genes involved in cortical growth, endocrine, and circadian pathways. These data place the GSK3b/PGC-1a axis centrally in a growth and metabolism network that is directly relevant to brain aging.

DOI: https://doi.org/10.1101/2023.09.29.559526