bims-midtic 2024-03-03 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024‒03‒03
nineteen papers selected by
Omkar Joshi, Turku Bioscience

A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
Mitochondria in disease: changes in shapes and dynamics.
Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.
Development of a signal-integrating reporter to monitor mitochondria-ER contacts.
Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.
Mitochondrial derived vesicles- Quo Vadis?
Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.
Changes in mitochondrial distribution occur at the axon initial segment in association with neurodegeneration in Drosophila.
ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.
ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.
Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP.
The hepatotoxicity of hexafluoropropylene oxide trimer acid caused by apoptosis via endoplasmic reticulum-mitochondrial crosstalk.
Genetic and bioinformatic analyses reveal transcriptional networks underlying dual genomic coordination of mitochondrial biogenesis.
Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.
Aging STINGs: mitophagy at the crossroads of neuroinflammation.
Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division.
Alterations in the molecular control of mitochondrial turnover in COPD lung and airway epithelial cells.
A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.
Miro1 improves the exogenous engraftment efficiency and therapeutic potential of mitochondria transfer using Wharton's jelly mesenchymal stem cells.

Nat Commun. 2024 Feb 28. 15(1): 1799

A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.

Sun Woo Sophie Kang, Rory P Cunningham, Colin B Miller, Lauryn A Brown, Constance M Cultraro, Adam Harned, Kedar Narayan, Jonathan Hernandez, Lisa M Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.

In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.

DOI: https://doi.org/10.1038/s41467-024-45751-9
Trends Biochem Sci. 2024 Feb 23. pii: S0968-0004(24)00031-8. [Epub ahead of print]

Mitochondria in disease: changes in shapes and dynamics.

Brenita C Jenkins, Kit Neikirk, Prasanna Katti, Steven M Claypool, Annet Kirabo, Melanie R McReynolds, Antentor Hinton.

  Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g., donuts, megamitochondria (MGs), and nanotunnels] and crista dynamics. This review explores the significance of dynamic alterations in mitochondrial morphology and regulators of mitochondrial and cristae shape. We focus on studies across tissue types and also describe new microscopy techniques for detecting mitochondrial morphologies both in vivo and in vitro that can improve understanding of mitochondrial structure. We highlight the potential therapeutic benefits of regulating mitochondrial morphology and discuss prospective avenues to restore mitochondrial bioenergetics to manage diseases related to mitochondrial dysfunction.

Keywords:  clinical diagnostics; contact sites; cristae dynamics; microscopy; mitochondrial morphology; mitochondrial shapes

DOI:  https://doi.org/10.1016/j.tibs.2024.01.011
Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2313540121

Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.

Mohamed A Eldeeb, Andrew N Bayne, Armaan Fallahi, Thomas Goiran, Emma J MacDougall, Andrea Soumbasis, Cornelia E Zorca, Jace-Jones Tabah, Rhalena A Thomas, Nathan Karpilovsky, Meghna Mathur, Thomas M Durcan, Jean-François Trempe, Edward A Fon.

  Mutations in PTEN-induced putative kinase 1 (PINK1) cause autosomal recessive early-onset Parkinson's disease (PD). PINK1 is a Ser/Thr kinase that regulates mitochondrial quality control by triggering mitophagy mediated by the ubiquitin (Ub) ligase Parkin. Upon mitochondrial damage, PINK1 accumulates on the outer mitochondrial membrane forming a high-molecular-weight complex with the translocase of the outer membrane (TOM). PINK1 then phosphorylates Ub, which enables recruitment and activation of Parkin followed by autophagic clearance of the damaged mitochondrion. Thus, Parkin-dependent mitophagy hinges on the stable accumulation of PINK1 on the TOM complex. Yet, the mechanism linking mitochondrial stressors to PINK1 accumulation and whether the translocases of the inner membrane (TIMs) are also involved remain unclear. Herein, we demonstrate that mitochondrial stress induces the formation of a PINK1-TOM-TIM23 supercomplex in human cultured cell lines, dopamine neurons, and midbrain organoids. Moreover, we show that PINK1 is required to stably tether the TOM to TIM23 complexes in response to stress such that the supercomplex fails to accumulate in cells lacking PINK1. This tethering is dependent on an interaction between the PINK1 N-terminal-C-terminal extension module and the cytosolic domain of the Tom20 subunit of the TOM complex, the disruption of which, by either designer or PD-associated PINK1 mutations, inhibits downstream mitophagy. Together, the findings provide key insight into how PINK1 interfaces with the mitochondrial import machinery, with important implications for the mechanisms of mitochondrial quality control and PD pathogenesis.

Keywords:  PINK1; mitochondrial import; mitochondrial quality control; mitophagy; proteolysis

DOI:  https://doi.org/10.1073/pnas.2313540121
bioRxiv. 2024 Feb 14. pii: 2024.02.14.580376. [Epub ahead of print]

Development of a signal-integrating reporter to monitor mitochondria-ER contacts.

Zheng Yang, David C Chan.

Mitochondria-ER contact sites (MERCS) serve as hotspots for important cellular processes, including calcium homeostasis, phospholipid homeostasis, mitochondria dynamics, and mitochondrial quality control. MERCS reporters based on complementation of GFP fragments have been designed to visualize MERCS in real-time, but we find that they do not accurately respond to changes in MERCS content. Here, we utilize split LacZ complementing fragments to develop the first MERCS reporter system (termed SpLacZ-MERCS) that continuously integrates the MERCS information within a cell and generates a fluorescent output. Our system exhibits good organelle targeting, no artifactual tethering, and effective, dynamic tracking of the MERCS level in single cells. The SpLacZ-MERCS reporter was validated by drug treatments and genetic perturbations known to affect mitochondria-ER contacts. The signal-integrating nature of SpLacZ-MERCS may enable systematic identification of genes and drugs that regulate mitochondria-ER interactions. Our successful application of the split LacZ complementation strategy to study MERCS may be extended to study other forms of inter-organellar crosstalk.

DOI: https://doi.org/10.1101/2024.02.14.580376
Brain Res. 2024 Feb 23. pii: S0006-8993(24)00080-5. [Epub ahead of print] 148826

Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.

Xiao-Rui Xi, Zhi-Qiang Zhang, Yan-Li Li, Zheng Liu, Dong-Yang Ma, Zan Gao, Shan Zhang.

  Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidence and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.

Keywords:  Hypothermia; Mitochondrial transfer; Oxygen–glucose deprivation/reoxygenation (OGD/R); Tunneling nanotubes (TNTs)

DOI:  https://doi.org/10.1016/j.brainres.2024.148826
FEBS J. 2024 Feb 27.

Mitochondrial derived vesicles- Quo Vadis?

Reut Hazan Ben-Menachem, Ophry Pines, Ann Saada.

  Mitochondria are dynamic, intracellular organelles with a separate genome originating from prokaryotes. They perform numerous functions essential for cellular metabolism and energy production. Mitochondrial-derived vesicles (MDVs) are single or double membrane-enclosed vesicles, formed and released from the mitochondrial sub-compartments into the cytosol, in response to various triggers. MDVs interact with other organelles such as lysosomes and peroxisomes or may be incorporated and excreted via extracellular vesicles (EVs). MDVs selectively incorporate diverse protein and lipid cargoes and are involved in various functions such as mitochondrial quality control, immunomodulation, energy complementation, and compartmentalization and transport. This review aims to provide a summary of the current knowledge of MDVs biogenesis, release, cargoes, and roles.

Keywords:  membrane; mitochondria; mitochondrial-derived vesicles

DOI:  https://doi.org/10.1111/febs.17103
iScience. 2024 Mar 15. 27(3): 109164

Optic atrophy 1 mediates muscle differentiation by promoting a metabolic switch via the supercomplex assembly factor SCAF1.

Matthew Triolo, Nicole Baker, Soniya Agarwal, Nikita Larionov, Tina Podinić, Mireille Khacho.

  Myogenic differentiation is integral for the regeneration of skeletal muscle following tissue damage. Though high-energy post-mitotic muscle relies predominantly on mitochondrial respiration, the importance of mitochondrial remodeling in enabling muscle differentiation and the players involved are not fully known. Here we show that the mitochondrial fusion protein OPA1 is essential for muscle differentiation. Our study demonstrates that OPA1 loss or inhibition, through genetic and pharmacological means, abolishes in vivo muscle regeneration and in vitro myotube formation. We show that both the inhibition and genetic deletion of OPA1 prevent the early onset metabolic switch required to drive myoblast differentiation. In addition, we observe an OPA1-dependent upregulation of the supercomplex assembly factor, SCAF1, at the onset of differentiation. Importantly, preventing the upregulation of SCAF1, through OPA1 loss or siRNA-mediated SCAF1 knockdown, impairs metabolic reprogramming and muscle differentiation. These findings reveal the integral role of OPA1 and mitochondrial reprogramming at the onset of myogenic differentiation.

Keywords:  Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109164
bioRxiv. 2024 Feb 14. pii: 2024.02.14.580288. [Epub ahead of print]

Changes in mitochondrial distribution occur at the axon initial segment in association with neurodegeneration in Drosophila.

Andrew P K Wodrich, Brent T Harris, Edward Giniger.

  Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a neurodegenerative phenotype and is known to affect several mitochondrial properties. Therefore, we investigated whether alterations of mitochondrial distribution are involved in Cdk5-associated neurodegeneration. We find that reducing Cdk5 activity does not alter the balance of mitochondrial localization to the somatodendritic vs. axonal neuronal compartments of the mushroom body, the learning and memory center of the Drosophila brain. We do, however, observe changes in mitochondrial distribution at the axon initial segment (AIS), a neuronal compartment located in the proximal axon involved in neuronal polarization and action potential initiation. Specifically, we observe that mitochondria are partially excluded from the AIS in wild-type neurons, but that this exclusion is lost upon reduction of Cdk5 activity, concomitant with the shrinkage of the AIS domain that is known to occur in this condition. This mitochondrial redistribution into the AIS is not likely due to the shortening of the AIS domain itself but rather due to altered Cdk5 activity. Furthermore, mitochondrial redistribution into the AIS is unlikely to be an early driver of neurodegeneration in the context of reduced Cdk5 activity.

Keywords:  Axon initial segment (AIS); Cdk5; Mitochondria; Mitochondrial distribution; Neurodegeneration

DOI:  https://doi.org/10.1101/2024.02.14.580288
J Cell Physiol. 2024 Feb 28.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Antentor Hinton, Prasanna Katti, Margaret Mungai, Duane D Hall, Olha Koval, Jianqiang Shao, Zer Vue, Edgar Garza Lopez, Rahmati Rostami, Kit Neikirk, Jessica Ponce, Jennifer Streeter, Brandon Schickling, Serif Bacevac, Chad Grueter, Andrea Marshall, Heather K Beasley, Young Do Koo, Sue C Bodine, Nayeli G Reyes Nava, Anita M Quintana, Long-Sheng Song, Isabella M Grumbach, Renata O Pereira, Brian Glancy, E Dale Abel.

  Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+ , lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Keywords:  activating transcription factor 4; endoplasmic reticulum; integrated stress response; interorganelle communication; mitochondria

DOI:  https://doi.org/10.1002/jcp.31204
J Biol Chem. 2024 Feb 26. pii: S0021-9258(24)01615-6. [Epub ahead of print] 107120

ORMDL3 regulates NLRP3 inflammasome activation by maintaining ER-mitochondria contacts in human macrophages and dictates ulcerative colitis patient outcome.

Jyotsna Sharma, Shaziya Khan, Nishakumari C Singh, Shikha Sahu, Desh Raj, Shakti Prakash, Pamela Bandyopadhyay, Kabita Sarkar, Vivek Bhosale, Tulika Chandra, Kumaravelu Jagavelu, Manoj Kumar Barthwal, Shashi Kumar Gupta, Mrigank Srivastava, Rajdeep Guha, Veena Ammanathan, Uday C Ghoshal, Kalyan Mitra, Amit Lahiri.

Genome-wide association studies in inflammatory bowel disease have identified risk loci in the Orosomucoid like 3 (ORMDL3) gene to confer susceptibility to ulcerative colitis (UC), but the underlying functional relevance remains unexplored. Here, we found that a subpopulation of the UC patients who had higher disease activity shows enhanced expression of ORMDL3 compared to the patients with lower disease activity and the non-UC controls. We also found that the patients showing high ORMDL3 mRNA expression have elevated IL-1β cytokine levels indicating positive correlation. Further, knockdown of ORMDL3 in the human monocyte-derived macrophages resulted in significantly reduced IL1β release. Mechanistically, we report for the first time that ORMDL3 contributes to a mounting inflammatory response via modulating mitochondrial morphology and activation of the NLRP3 inflammasome. Specifically, we observed an increased fragmentation of mitochondria and enhanced contacts with the ER during ORMDL3 over-expression, enabling efficient NLRP3 inflammasome activation. We show that ORMDL3 that was previously known to be localized in the ER, also becomes localized to mitochondria-associated membranes and mitochondria during inflammatory conditions. Additionally, ORMDL3 interacts with mitochondrial dynamic regulating protein Fis-1 present in the mitochondria-associated membrane. Accordingly, knockdown of ORMDL3 in a dextran sodium sulfate (DSS)-induced colitis mouse model showed reduced colitis severity. Taken together, we have uncovered a functional role for ORMDL3 in mounting inflammation during UC pathogenesis by modulating ER-mitochondrial contact and dynamics.

DOI: https://doi.org/10.1016/j.jbc.2024.107120
bioRxiv. 2024 Feb 13. pii: 2024.02.12.579972. [Epub ahead of print]

Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP.

Yusuke Hirabayashi, Tommy L Lewis, Yudan Du, Daniel M Virga, Aubrianna M Decker, Giovanna Coceano, Jonatan Alvelid, Maëla A Paul, Stevie Hamilton, Parker Kneis, Yasufumi Takahashi, Jellert T Gaublomme, Ilaria Testa, Franck Polleux.

In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. Here, we demonstrate using multiple, independent, in vitro and in vivo approaches that the majority (~80-90%) of axonal mitochondria in cortical pyramidal neurons (CPNs), lack mitochondrial DNA (mtDNA). Using dynamic, optical imaging analysis of genetically encoded sensors for mitochondrial matrix ATP and pH, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial complex V (ATP synthase) functions in a reverse way, consuming ATP and protruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results demonstrate that in mammalian CPNs, axonal mitochondria do not play a major role in ATP supply, despite playing other functions critical to regulating neurotransmission such as Ca2+ buffering.

DOI: https://doi.org/10.1101/2024.02.12.579972
Sci Total Environ. 2024 Feb 28. pii: S0048-9697(24)01373-1. [Epub ahead of print] 171234

The hepatotoxicity of hexafluoropropylene oxide trimer acid caused by apoptosis via endoplasmic reticulum-mitochondrial crosstalk.

Jiayu Du, Xuliang Zhang, Bo Li, Siming Huo, Jian Zhang, Yang Fu, Miao Song, Bing Shao, Yanfei Li.

  As a ubiquitous pollutant in the environment, hexafluoropropylene oxide trimer acid (HFPO-TA) has been proven to have strong hepatotoxicity. However, the underlying mechanism is still unclear. Consequently, in vivo and in vitro models of HFPO-TA exposure were established to investigate the detrimental effects of HFPO-TA on the liver. In vivo, we discovered that HFPO-TA enhanced endoplasmic reticulum (ER)-mitochondrial association, caused mitochondrial oxidative damage, activated ER stress, and induced apoptosis in mouse livers. In vitro experiments confirmed that IP3R overexpression on ER structure increased mitochondrial calcium levels, which led to mitochondrial damage and mitochondria-dependent apoptosis in HepG2 cells exposed to HFPO-TA. Subsequently, damaged mitochondria released a large amount of mitochondrial ROS, which activated ER stress and ER stress-dependent apoptosis. In conclusion, this study demonstrates that HFPO-TA can induce apoptosis by regulating the crosstalk between ER and mitochondria, ultimately leading to liver damage. These findings reveal the significant hepatotoxicity of HFPO-TA and its potential mechanisms.

Keywords:  Apoptosis; ER-mitochondrial crosstalk; Hepatotoxicity; Hexafluoropropylene oxide trimer acid

DOI:  https://doi.org/10.1016/j.scitotenv.2024.171234
bioRxiv. 2024 Jan 29. pii: 2024.01.25.577217. [Epub ahead of print]

Genetic and bioinformatic analyses reveal transcriptional networks underlying dual genomic coordination of mitochondrial biogenesis.

Fan Zhang, Annie Lee, Anna Freitas, Jake Herb, Zongheng Wang, Snigdha Gupta, Zhe Chen, Hong Xu.

Mitochondrial genome encodes handful genes of respiratory chain complexes, whereas all the remaining mitochondrial proteins are encoded on the nuclear genome. However, the mechanisms coordinating these two genomes to control mitochondrial biogenesis remain largely unknown. To identify transcription circuits involved in these processes, we performed a candidate RNAi screen in developing eyes that had reduced mitochondrial DNA contents. We reasoned that impaired mitochondrial biogenesis would synergistically interact with mtDNA deficiency in disrupting tissue development. Over 638 transcription factors annotated in the fly genome, we identified 77 transcription factors that may be involved in mitochondrial genome maintenance and gene expression. Additional genetic and genomic analyses revealed that a novel transcription factor, CG1603, and its upstream factor YL-1 are essential for mitochondrial biogenesis. We constructed a regulator network among positive hits using the published CHIP-seq data. The network analysis revealed extensive connections, and complex hierarchical organization underlying the transcription regulation of mitochondrial biogenesis.

DOI: https://doi.org/10.1101/2024.01.25.577217
EMBO Rep. 2024 Mar 01.

Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model.

Callum Dark, Nashia Ali, Sofya Golenkina, Vaibhav Dhyani, Ronnie Blazev, Benjamin L Parker, Kate T Murphy, Gordon S Lynch, Tarosi Senapati, S Sean Millard, Sarah M Judge, Andrew R Judge, Lopamudra Giri, Sarah M Russell, Louise Y Cheng.

  Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homologue ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.

Keywords:   Drosophila ; Cachexia; Lipid Metabolism; Muscle

DOI:  https://doi.org/10.1038/s44319-024-00102-z
Autophagy. 2024 Feb 27.

Aging STINGs: mitophagy at the crossroads of neuroinflammation.

Juan Ignacio Jiménez-Loygorri, Patricia Boya.

  Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in non-selective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.

Keywords:  Inflammation; PINK1; Parkin; mitochondria; mtDNA; retina

DOI:  https://doi.org/10.1080/15548627.2024.2322421
iScience. 2024 Mar 15. 27(3): 109189

Chemical inhibition of phosphatidylcholine biogenesis reveals its role in mitochondrial division.

Hiroya Shiino, Shinya Tashiro, Michiko Hashimoto, Yuki Sakata, Takamitsu Hosoya, Toshiya Endo, Hirotatsu Kojima, Yasushi Tamura.

  Phospholipids are major components of biological membranes and play structural and regulatory roles in various biological processes. To determine the biological significance of phospholipids, the use of chemical inhibitors of phospholipid metabolism offers an effective approach; however, the availability of such compounds is limited. In this study, we performed a chemical-genetic screening using yeast and identified small molecules capable of inhibiting phosphatidylcholine (PC) biogenesis, which we designated PC inhibitors 1, 2, 3, and 4 (PCiB-1, 2, 3, and 4). Biochemical analyses indicated that PCiB-2, 3, and 4 inhibited the phosphatidylethanolamine (PE) methyltransferase activity of Cho2, whereas PCiB-1 may inhibit PE transport from mitochondria to the endoplasmic reticulum (ER). Interestingly, we found that PCiB treatment resulted in mitochondrial fragmentation, which was suppressed by expression of a dominant-negative mutant of the mitochondrial division factor Dnm1. These results provide evidence that normal PC biogenesis is important for the regulation of mitochondrial division.

Keywords:  Biochemistry; Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109189
Sci Rep. 2024 02 27. 14(1): 4821

Alterations in the molecular control of mitochondrial turnover in COPD lung and airway epithelial cells.

Christy B M Tulen, Cheryl van de Wetering, Caspar H J Schiffers, Ellen Weltjens, Birke J Benedikter, Pieter A Leermakers, Juliana H Boukhaled, Marie-José Drittij, Bernd T Schmeck, Niki L Reynaert, Antoon Opperhuizen, Frederik-Jan van Schooten, Alexander H V Remels.

  Abnormal mitochondria have been observed in bronchial- and alveolar epithelial cells of patients with chronic obstructive pulmonary disease (COPD). However, it is unknown if alterations in the molecular pathways regulating mitochondrial turnover (mitochondrial biogenesis vs mitophagy) are involved. Therefore, in this study, the abundance of key molecules controlling mitochondrial turnover were assessed in peripheral lung tissue from non-COPD patients (n = 6) and COPD patients (n = 11; GOLDII n = 4/11; GOLDIV n = 7/11) and in both undifferentiated and differentiated human primary bronchial epithelial cells (PBEC) from non-COPD patients and COPD patients (n = 4-7 patients/group). We observed significantly decreased transcript levels of key molecules controlling mitochondrial biogenesis (PPARGC1B, PPRC1, PPARD) in peripheral lung tissue from severe COPD patients. Interestingly, mRNA levels of the transcription factor TFAM (mitochondrial biogenesis) and BNIP3L (mitophagy) were increased in these patients. In general, these alterations were not recapitulated in undifferentiated and differentiated PBECs with the exception of decreased PPARGC1B expression in both PBEC models. Although these findings provide valuable insight in these pathways in bronchial epithelial cells and peripheral lung tissue of COPD patients, whether or not these alterations contribute to COPD pathogenesis, underlie changes in mitochondrial function or may represent compensatory mechanisms remains to be established.

Keywords:  Chronic obstructive pulmonary disease; Mitochondrial biogenesis; Mitophagy; Peripheral lung tissue; Primary bronchial epithelial cells

DOI:  https://doi.org/10.1038/s41598-024-55335-8
bioRxiv. 2024 Feb 15. pii: 2024.02.14.580336. [Epub ahead of print]

A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.

Philip J Mannino, Andrew Perun, Ivan Surovstev, Nicholas R Ader, Lin Shao, Thomas J Melia, Megan C King, C Patrick Lusk.

Autophagic mechanisms that maintain nuclear envelope homeostasis are bulwarks to aging and disease. By leveraging 4D lattice light sheet microscopy and correlative light and electron tomography, we define a quantitative and ultrastructural timeline of a nuclear macroautophagy (nucleophagy) pathway in yeast. Nucleophagy initiates with a rapid local accumulation of the nuclear cargo adaptor Atg39 at the nuclear envelope adjacent to the nucleus-vacuole junction and is delivered to the vacuole in ~300 seconds through an autophagosome intermediate. Mechanistically, nucleophagy incorporates two consecutive and genetically defined membrane fission steps: inner nuclear membrane (INM) fission generates a lumenal vesicle in the perinuclear space followed by outer nuclear membrane (ONM) fission to liberate a double membraned vesicle to the cytosol. ONM fission occurs independently of phagophore engagement and instead relies surprisingly on dynamin-like protein1 (Dnm1), which is recruited to sites of Atg39 accumulation at the nuclear envelope. Loss of Dnm1 compromises nucleophagic flux by stalling nucleophagy after INM fission. Our findings reveal how nuclear and INM cargo are removed from an intact nucleus without compromising its integrity, achieved in part by a non-canonical role for Dnm1 in nuclear envelope remodeling.

DOI: https://doi.org/10.1101/2024.02.14.580336
Mitochondrion. 2024 Feb 24. pii: S1567-7249(24)00014-X. [Epub ahead of print] 101856

Miro1 improves the exogenous engraftment efficiency and therapeutic potential of mitochondria transfer using Wharton's jelly mesenchymal stem cells.

Yu-Han Lin, Kai-Lieh Lin, Xiao-Wen Wang, Jong-Jer Lee, Feng-Sheng Wang, Pei-Wen Wang, Min-Yu Lan, Chia-Wei Liou, Tsu-Kung Lin.

  Mitochondria are important for maintaining cellular energy metabolism and regulating cellular senescence. Mitochondrial DNA (mtDNA) encodes subunits of the OXPHOS complexes which are essential for cellular respiration and energy production. Meanwhile, mtDNA variants have been associated with the pathogenesis of neurodegenerative diseases, including MELAS, for which no effective treatment has been developed. To alleviate the pathological conditions involved in mitochondrial disorders, mitochondria transfer therapy has shown promise. Wharton's jelly mesenchymal stem cells (WJMSCs) have been identified as suitable mitochondria donors for mitochondria-defective cells, wherein mitochondrial functions can be rescued. Miro1 participates in mitochondria trafficking by anchoring mitochondria to microtubules. In this study, we identified Miro1 over-expression as a factor that could help to enhance the efficiency of mitochondrial delivery. More specifically, we reveal that Miro1 over-expressed WJMSCs significantly improved intercellular communications, cell proliferation rates, and mitochondrial membrane potential, while restoring mitochondrial bioenergetics in mitochondria-defective fibroblasts. Furthermore, Miro1 over-expressed WJMSCs decreased rates of induced apoptosis and ROS production in MELAS fibroblasts; although, Miro1 over-expression did not rescue mtDNA mutation ratios nor mitochondrial biogenesis. This study presents a potentially novel therapeutic strategy for treating mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and other diseases associated with dysfunctional mitochondria, while the pathophysiological relevance of our results should be further verified by animal models and clinical studies.

Keywords:  MELAS; Miro1; Mitochondria; Mitochondrial bioenergetics; WJMSCs

DOI:  https://doi.org/10.1016/j.mito.2024.101856