bims-cesemi 2024-09-01 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–09–01
eightteen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Calcium tunneling through the ER and transfer to other organelles for optimal signaling in Toxoplasma gondii.
A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases.
Cellular senescence is required for cardiac regeneration.
IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.
P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
TRPM7 controls skin keratinocyte senescence by targeting intracellular calcium signaling.
Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease.
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.
Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?
Mitochondrial membrane lipids in the regulation of bioenergetic flux.
Egr1 regulates regenerative senescence and cardiac repair.
Premature senescence is regulated by crosstalk among TFEB, the autophagy lysosomal pathway and ROS derived from damaged mitochondria in NaAsO2-exposed auditory cells.
Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.
INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.
Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis.

bioRxiv. 2024 Aug 15. pii: 2024.08.15.608087. [Epub ahead of print]

Calcium tunneling through the ER and transfer to other organelles for optimal signaling in Toxoplasma gondii.

Zhu-Hong Li, Beejan Asady, Le Chang, Miryam Andrea Hortua Triana, Catherine Li, Isabelle Coppens, Silvia N J Moreno.

  Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or the endoplasmic reticulum (ER) and results in a dramatic increase in the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial Ca2+ levels are well regulated to enable precise and specific activation of critical biological processes. Ca2+ signaling regulates pathogenic features of apicomplexan parasites like Toxoplasma gondii which infects approximately one-third of the world's population. T. gondii relies on Ca2+ signals to stimulate traits of its infection cycle and several Ca2+ signaling elements play essential roles in its parasitic cycle. Active egress, an essential step for the infection cycle of T. gondii is preceded by a large increase in cytosolic Ca2+ most likely by release from intracellular stores. Intracellular parasites take up Ca2+ from the host cell during host Ca2+ signaling events to replenish intracellular stores. In this work, we investigated the mechanism by which intracellular stores are replenished with Ca2+ and demonstrated a central role for the SERCA-Ca2+-ATPase to keep not only the ER filled with Ca2+ but also acidic stores. We also show mitochondrial Ca2+ uptake, by transfer of Ca2+ from the ER most likely through membrane contact sites. We propose a central role for the ER in tunneling of calcium from the extracellular milieu through the ER to other organelles.

Keywords:  Calcium; SERCA-Ca2+-ATPase; Toxoplasma gondii; calcium tunneling; endoplasmic reticulum; membrane contact sites

DOI:  https://doi.org/10.1101/2024.08.15.608087
Cell Metab. 2024 Aug 15. pii: S1550-4131(24)00327-9. [Epub ahead of print]

A nutrigeroscience approach: Dietary macronutrients and cellular senescence.

Mariah F Calubag, Paul D Robbins, Dudley W Lamming.

  Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.

Keywords:  branched-chain amino acids; cellular senescence; healthspan; macronutrients; nutrigeroscience; protein; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.cmet.2024.07.025
Trends Endocrinol Metab. 2024 Aug 27. pii: S1043-2760(24)00191-7. [Epub ahead of print]

Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases.

Azadeh Nasuhidehnavi, Weronika Zarzycka, Ignacy Górecki, Ying Ann Chiao, Chi Fung Lee.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for redox reactions and regulates cellular catabolic pathways. An intertwined relationship exists between NAD+ and mitochondria, with consequences for mitochondrial function. Dysregulation in NAD+ homeostasis can lead to impaired energetics and increased oxidative stress, contributing to the pathogenesis of cardiometabolic diseases. In this review, we explore how disruptions in NAD+ homeostasis impact mitochondrial function in various cardiometabolic diseases. We discuss emerging studies demonstrating that enhancing NAD+ synthesis or inhibiting its consumption can ameliorate complications of this family of pathological conditions. Additionally, we highlight the potential role and therapeutic promise of mitochondrial NAD+ transporters in regulating cellular and mitochondrial NAD+ homeostasis.

DOI: https://doi.org/10.1016/j.tem.2024.07.010
Nat Cardiovasc Res. 2024 Aug;3(8): 897-898

Cellular senescence is required for cardiac regeneration.

DOI: https://doi.org/10.1038/s44161-024-00494-0
Theriogenology. 2024 Aug 19. pii: S0093-691X(24)00344-3. [Epub ahead of print]229 147-157

IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.

Chang Zhang, Xiaoqing Sun, Deyi Wu, Guoxia Wang, Hainan Lan, Xin Zheng, Suo Li.

  Calcium ions (Ca2+) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP3R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca2+ levels. However, the mechanism by which IP3R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP3R1 to investigate the effects of IP3R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP3R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca2+ ([Ca2+]m) transport network protein IP3R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP3R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP3R1 interference, resulting in the accumulation of large amounts of [Ca2+]m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca2+]m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca2+ overload were improved. In conclusion, our results indicated IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.

Keywords:  Ca(2+); ER; IP(3)R1; Mitochondria; Porcine oocytes; ROS

DOI:  https://doi.org/10.1016/j.theriogenology.2024.08.023
Nat Commun. 2024 Aug 28. 15(1): 7458

P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.

Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.

DOI: https://doi.org/10.1038/s41467-024-51901-w
FEBS J. 2024 Aug 26.

TRPM7 controls skin keratinocyte senescence by targeting intracellular calcium signaling.

Xingjie Ma, Dandan Qi, Xiaoming Sun, Yue Gao, Jiang Ma, Jinghui Yang, Qingtong Shi, Guangfa Wei, Hualing Li, Weili Liu, Juping Chen.

  Cellular senescence is described as an irreversible cell cycle arrest for proliferating cells and is associated with the secretion of senescence associated secretory phenotype factors. It has been known to accumulate with age and is regarded as a key driver of aging-associated skin pathologies. However, the lack of markers of skin senescence and partially understood skin cellular senescence mechanisms has limited the exploration of skin aging and anti-skin aging strategies. Recently, intracellular calcium signaling has emerged as an important regulator of cellular senescence and aging. However, little is known about the modulation of skin cellular senescence by calcium-associated factors. Here, we found that the expression of calcium channel transient receptor potential melastatin 7 (TRPM7) is elevated during skin keratinocyte senescence and aging. Importantly, TRPM7 promotes skin keratinocyte senescence by triggering intracellular calcium transfer from the endoplasmic reticulum to the mitochondria; accumulation of mitochondrial calcium then induces a drop in mitochondrial membrane potential and reactive oxygen species production, leading to subsequent nuclear enlargement and DNA damage. Altogether, these findings indicate that TRPM7 controls skin keratinocyte senescence through regulating intracellular calcium signaling, and thus, shed light on novel strategies for anti-skin aging therapy.

Keywords:  DNA damage; ROS; TRPM7; calcium signaling; skin cellular senescence

DOI:  https://doi.org/10.1111/febs.17252
Nat Commun. 2024 Aug 27. 15(1): 7352

Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.

William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.

The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.

DOI: https://doi.org/10.1038/s41467-024-51680-4
Nat Cardiovasc Res. 2024 May;3(5): 500-514

Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease.

Tyler L Stevens, Henry M Cohen, Joanne F Garbincius, John W Elrod.

The mitochondrial calcium (mCa2+) uniporter channel (mtCU) resides at the inner mitochondrial membrane and is required for Ca2+ to enter the mitochondrial matrix. The mtCU is essential for cellular function, as mCa2+ regulates metabolism, bioenergetics, signaling pathways and cell death. mCa2+ uptake is primarily regulated by the MICU family (MICU1, MICU2, MICU3), EF-hand-containing Ca2+-sensing proteins, which respond to cytosolic Ca2+ concentrations to modulate mtCU activity. Considering that mitochondrial function and Ca2+ signaling are ubiquitously disrupted in cardiovascular disease, mtCU function has been a hot area of investigation for the last decade. Here we provide an in-depth review of MICU-mediated regulation of mtCU structure and function, as well as potential mtCU-independent functions of these proteins. We detail their role in cardiac physiology and cardiovascular disease by highlighting the phenotypes of different mutant animal models, with an emphasis on therapeutic potential and targets of interest in this pathway.

DOI: https://doi.org/10.1038/s44161-024-00463-7
Nat Commun. 2024 Aug 27. 15(1): 7378

Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.

Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.

DOI: https://doi.org/10.1038/s41467-024-51363-0
EMBO Rep. 2024 Aug 27.

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel.

  Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

Keywords:   DNM1L ; Alternative Splice Variants; Drp1; Mitochondrial Fission; Ovarian Cancer

DOI:  https://doi.org/10.1038/s44319-024-00232-4
Aging Cell. 2024 Aug 26. e14296

Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?

Antentor O Hinton, Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano.

  The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.

Keywords:  aging; mitochondria; organelle contacts; protein targeting; structure

DOI:  https://doi.org/10.1111/acel.14296
Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]

Mitochondrial membrane lipids in the regulation of bioenergetic flux.

Stephen Thomas Decker, Katsuhiko Funai.

  Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.

Keywords:  bioenergetics; mitochondria; phospholipids

DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
Nat Cardiovasc Res. 2024 Aug;3(8): 915-932

Egr1 regulates regenerative senescence and cardiac repair.

Lingling Zhang, Jacob Elkahal, Tianzhen Wang, Racheli Rimmer, Alexander Genzelinakh, Elad Bassat, Jingkui Wang, Dahlia Perez, David Kain, Daria Lendengolts, Roni Winkler, Hanna Bueno-Levy, Kfir Baruch Umansky, David Mishaly, Avraham Shakked, Shoval Miyara, Avital Sarusi-Portuguez, Naomi Goldfinger, Amir Prior, David Morgenstern, Yishai Levin, Yoseph Addadi, Baoguo Li, Varda Rotter, Uriel Katz, Elly M Tanaka, Valery Krizhanovsky, Rachel Sarig, Eldad Tzahor.

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.

DOI: https://doi.org/10.1038/s44161-024-00493-1
Cell Death Discov. 2024 Aug 28. 10(1): 382

Premature senescence is regulated by crosstalk among TFEB, the autophagy lysosomal pathway and ROS derived from damaged mitochondria in NaAsO2-exposed auditory cells.

Yuna Suzuki, Ken Hayashi, Fumiyuki Goto, Yasuyuki Nomura, Chisato Fujimoto, Makoto Makishima.

Age-related hearing loss (ARHL) is one of the most prevalent types of sensory decline in a superaging society. Although various studies have focused on the effect of oxidative stress on the inner ear as an inducer of ARHL, there are no effective preventive approaches for ARHL. Recent studies have suggested that oxidative stress-induced DNA damage responses (oxidative DDRs) drive cochlear cell senescence and contribute to accelerated ARHL, and autophagy could function as a defense mechanism against cellular senescence in auditory cells. However, the underlying mechanism remains unclear. Sodium arsenite (NaAsO2) is a unique oxidative stress inducer associated with reactive oxygen species (ROS) that causes high-tone hearing loss similar to ARHL. Transcription factor EB (TFEB) functions as a master regulator of the autophagy‒lysosome pathway (ALP), which is a potential target during aging and the pathogenesis of various age-related diseases. Here, we focused on the function of TFEB and the impact of intracellular ROS as a potential target for ARHL treatment in a NaAsO2-induced auditory premature senescence model. Our results suggested that short exposure to NaAsO2 leads to DNA damage, lysosomal damage and mitochondrial damage in auditory cells, triggering temporary signals for TFEB transport into the nucleus and, as a result, causing insufficient autophagic flux and declines in lysosomal function and biogenesis and mitochondrial quality. Then, intracellular ROS derived from damaged mitochondria play a role as a second messenger to induce premature senescence in auditory cells. These findings suggest that TFEB activation via transport into the nucleus contributes to anti-senescence activity in auditory cells and represents a new therapeutic target for ARHL. We have revealed the potential function of TFEB as a master regulator of the induction of oxidative stress-induced premature senescence and the senescence-associated secretion phenotype (SASP) in auditory cells, which regulates ALP and controls mitochondrial quality through ROS production.

DOI: https://doi.org/10.1038/s41420-024-02139-4
Curr Top Membr. 2024 ;pii: S1063-5823(24)00020-6. [Epub ahead of print]93 85-116

Lysosomal membrane contact sites: Integrative hubs for cellular communication and homeostasis.

Sumit Bandyopadhyay, Daniel Adebayo, Eseiwi Obaseki, Hanaa Hariri.

  Lysosomes are more than just cellular recycling bins; they play a crucial role in regulating key cellular functions. Proper lysosomal function is essential for growth pathway regulation, cell proliferation, and metabolic homeostasis. Impaired lysosomal function is associated with lipid storage disorders and neurodegenerative diseases. Lysosomes form extensive and dynamic close contacts with the membranes of other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets. These membrane contacts sites (MCSs) are vital for many lysosomal functions. In this chapter, we will explore lysosomal MCSs focusing on the machinery that mediates these contacts, how they are regulated, and their functional implications on physiology and pathology.

Keywords:  Lipid homeostasis; Lysosomes; Membrane contact sites; Nutrient sensing; Organelles communication

DOI:  https://doi.org/10.1016/bs.ctm.2024.07.001
Res Sq. 2024 Aug 16. pii: rs.3.rs-4720604. [Epub ahead of print]

INF2-mediated actin polymerization at ER-organelle contacts regulates organelle size and movement.

Cara R Schiavon, Yuning Wang, Jasmine W Feng, Stephanie Garrett, Tsung-Chang Sung, Yelena Dayn, Chunxin Wang, Richard J Youle, Omar A Quintero-Carmona, Gerald S Shadel, Uri Manor.

Proper regulation of organelle dynamics and inter-organelle contacts is critical for cellular health and function. Both the endoplasmic reticulum (ER) and actin cytoskeleton are known to regulate organelle dynamics, but how, when, and where these two subcellular components are coordinated to control organelle dynamics remains unclear. Here, we show that ER-associated actin consistently marks mitochondrial, endosomal, and lysosomal fission sites. We also show that actin polymerization by the ER-anchored isoform of the formin protein INF2 is a key regulator of the morphology and mobility of these organelles. Together, our findings establish a mechanism by which INF2-mediated polymerization of ER-associated actin at ER-organelle contacts regulates organelle dynamics.

DOI: https://doi.org/10.21203/rs.3.rs-4720604/v1
Mol Metab. 2024 Aug 27. pii: S2212-8778(24)00146-7. [Epub ahead of print] 102015

Loss of mitochondria long-chain fatty acid oxidation impairs skeletal muscle contractility by disrupting myofibril structure and calcium homeostasis.

Andrea S Pereyra, Regina F Fernandez, Adam Amorese, Jasmine N Castro, Chien-Te Lin, Espen E Spangenburg, Jessica M Ellis.

  Abnormal lipid metabolism in mammalian tissues can be highly deleterious, leading to organ failure. Carnitine Palmitoyltransferase 2 (CPT2) deficiency is an inherited metabolic disorder affecting the liver, heart, and skeletal muscle due to impaired mitochondrial oxidation of long-chain fatty acids (mLCFAO) for energy production. However, the basis of tissue damage in mLCFAO disorders is not fully understood. Mice lacking CPT2 in skeletal muscle (Cpt2Sk-/-) were generated to investigate the nexus between mFAO deficiency and myopathy. Compared to controls, ex-vivo contractile force was reduced by 70% in Cpt2Sk-/- oxidative soleus muscle despite the preserved capacity to couple ATP synthesis to mitochondrial respiration on alternative substrates to long-chain fatty acids. Increased mitochondrial biogenesis, lipid accumulation, and the downregulation of 80% of dystrophin-related and contraction-related proteins severely compromised the structure and function of Cpt2Sk-/- soleus. CPT2 deficiency affected oxidative muscles more than glycolytic ones. Exposing isolated sarcoplasmic reticulum to long-chain acylcarnitines (LCACs) inhibited calcium uptake. In agreement, Cpt2Sk-/- soleus had decreased calcium uptake and significant accumulation of palmitoyl-carnitine, suggesting that LCACs and calcium dyshomeostasis are linked in skeletal muscle. Our data demonstrate that loss of CPT2 and mLCFAO compromise muscle structure and function due to excessive mitochondrial biogenesis, downregulation of the contractile proteome, and disruption of calcium homeostasis.

Keywords:  CPT2; Calcium; Fatty acid oxidation; Muscle contraction; Palmitoyl-carnitine

DOI:  https://doi.org/10.1016/j.molmet.2024.102015