bims-midtic 2023-10-29 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2023–10–29
sixteen papers selected by
Omkar Joshi, Turku Bioscience

Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.
Role of Mitochondrial Dynamics in Heart Diseases.
The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.
Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.
The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.
Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.
CCDC127 regulates lipid droplet homeostasis by enhancing mitochondria-ER contacts.
Cadmium promotes nonalcoholic fatty liver disease by inhibiting intercellular mitochondrial transfer.
Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.
Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure.
Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.
Regulation of astrocyte metabolism by mitochondrial translocator protein 18kDa.
LAMC2 mitigates ER stress by enhancing ER-mitochondria interaction via binding to MYH9 and MYH10.
A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.
Poor communication between ER and mitochondria: a signature of ALS/FTD?
FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

J Biol Chem. 2023 Oct 20. pii: S0021-9258(23)02408-0. [Epub ahead of print] 105380

Human Fis1 directly interacts with Drp1 in an evolutionarily conserved manner to promote mitochondrial fission.

Kelsey A Nolden, Megan C Harwig, R Blake Hill.

  Mitochondrial Fission Protein 1 (Fis1) and Dynamin Related Protein 1 (Drp1) are the only two proteins evolutionarily conserved for mitochondrial fission, and directly interact in S. cerevisiae to facilitate membrane scission. However, it remains unclear if a direct interaction is conserved in higher eukaryotes as other Drp1 recruiters, not present in yeast, are known. Using NMR, differential scanning fluorimetry, and microscale thermophoresis, we determined that human Fis1 directly interacts with human Drp1 (KD = 12-68 μM), and appears to prevent Drp1 assembly, but not GTP hydrolysis. Similar to yeast, the Fis1-Drp1 interaction appears governed by two structural features of Fis1: its N-terminal arm and a conserved surface. Alanine scanning mutagenesis of the arm identified both loss- and gain-of-function alleles with mitochondrial morphologies ranging from highly elongated (N6A) to highly fragmented (E7A) demonstrating a profound ability of Fis1 to govern morphology in human cells. An integrated analysis identified a conserved Fis1 residue, Y76, that upon substitution to alanine, but not phenylalanine, also caused highly fragmented mitochondria. The similar phenotypic effects of the E7A and Y76A substitutions, along with NMR data, support that intramolecular interactions occur between the arm and a conserved surface on Fis1 to promote Drp1-mediated fission as in S. cerevisiae. These findings indicate that some aspects of Drp1-mediated fission in humans derive from direct Fis1-Drp1 interactions that are conserved across eukaryotes.

Keywords:  biophysics; cell biology; confocal microscopy; fission; microscale thermophoresis (MST); mitochondria; mitochondrial dynamics; nuclear magnetic resonance (NMR); protein-protein interaction

DOI:  https://doi.org/10.1016/j.jbc.2023.105380
Genes (Basel). 2023 Sep 26. pii: 1876. [Epub ahead of print]14(10):

Role of Mitochondrial Dynamics in Heart Diseases.

Takeshi Tokuyama, Shigeru Yanagi.

  Mitochondrial dynamics, including fission and fusion processes, are essential for heart health. Mitochondria, the powerhouses of cells, maintain their integrity through continuous cycles of biogenesis, fission, fusion, and degradation. Mitochondria are relatively immobile in the adult heart, but their morphological changes due to mitochondrial morphology factors are critical for cellular functions such as energy production, organelle integrity, and stress response. Mitochondrial fusion proteins, particularly Mfn1/2 and Opa1, play multiple roles beyond their pro-fusion effects, such as endoplasmic reticulum tethering, mitophagy, cristae remodeling, and apoptosis regulation. On the other hand, the fission process, regulated by proteins such as Drp1, Fis1, Mff and MiD49/51, is essential to eliminate damaged mitochondria via mitophagy and to ensure proper cell division. In the cardiac system, dysregulation of mitochondrial dynamics has been shown to cause cardiac hypertrophy, heart failure, ischemia/reperfusion injury, and various cardiac diseases, including metabolic and inherited cardiomyopathies. In addition, mitochondrial dysfunction associated with oxidative stress has been implicated in atherosclerosis, hypertension and pulmonary hypertension. Therefore, understanding and regulating mitochondrial dynamics is a promising therapeutic tool in cardiac diseases. This review summarizes the role of mitochondrial morphology in heart diseases for each mitochondrial morphology regulatory gene, and their potential as therapeutic targets to heart diseases.

Keywords:  Drp1; Mfn1; Mfn2; Opa1; cardiovascular diseases; fission and fusion; heart failure; mitochondrial dynamics

DOI:  https://doi.org/10.3390/genes14101876
Autophagy. 2023 Oct 24.

The NLRX1-SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn2+ trafficking.

Yu Song, Huaizhen Liang, Gaocai Li, Liang Ma, Dingchao Zhu, Weifeng Zhang, Bide Tong, Shuai Li, Yong Gao, Xinghuo Wu, Yukun Zhang, Xiaobo Feng, Kun Wang, Cao Yang.

  Intervertebral disc degeneration (IDD) is the most critical pathological factor in the development of low back pain. The maintenance of nucleus pulposus (NP) cell and intervertebral disc integrity benefits largely from well-controlled mitochondrial quality, surveilled by mitochondrial dynamics (fission and fusion) and mitophagy, but the outcome is cellular context-dependent that remain to be clarified. Our studies revealed that the loss of NLRX1 is correlated with NP cell senescence and IDD progression, which involve disordered mitochondrial quality. Further using animal and in vitro tissue and cell models, we demonstrated that NLRX1 could facilitate mitochondrial quality by coupling mitochondrial dynamic factors (p-DNM1L, L-OPA1:S-OPA1, OMA1) and mitophagy activity. Conversely, mitochondrial collapse occurred in NLRX1-defective NP cells and switched on the compensatory PINK1-PRKN pathway that led to excessive mitophagy and aggressive NP cell senescence. Mechanistically, NLRX1 was originally shown to interact with zinc transporter SLC39A7 and modulate mitochondrial Zn2+ trafficking via the formation of an NLRX1-SLC39A7 complex on the mitochondrial membrane of NP cells, subsequently orchestrating mitochondrial dynamics and mitophagy. The restoration of NLRX1 function by gene overexpression or pharmacological agonist (NX-13) treatment showed great potential for regulating mitochondrial fission with synchronous fusion and mitophagy, thus sustaining mitochondrial homeostasis, ameliorating NP cell senescence and rejuvenating intervertebral discs. Collectively, our findings highlight a working model whereby the NLRX1-SLC39A7 complex coupled mitochondrial dynamics and mitophagy activity to surveil and target damaged mitochondria for degradation, which determines the beneficial function of the mitochondrial surveillance system and ultimately rejuvenates intervertebral discs.

Keywords:  Intervertebral disc degeneration; NLRX1; SLC39A7; mitochondrial dynamics; mitophagy; nucleus pulposus

DOI:  https://doi.org/10.1080/15548627.2023.2274205
Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00336-7. [Epub ahead of print]

Blocking AMPKαS496 phosphorylation improves mitochondrial dynamics and hyperglycemia in aging and obesity.

Alexia Pearah, Balamurugan Ramatchandirin, Ting Liu, Risa M Wolf, Arisa Ikeda, Sally Radovick, Hiromi Sesaki, Fredric E Wondisford, Brian O'Rourke, Ling He.

  Impaired mitochondrial dynamics causes aging-related or metabolic diseases. Yet, the molecular mechanism responsible for the impairment of mitochondrial dynamics is still not well understood. Here, we report that elevated blood insulin and/or glucagon levels downregulate mitochondrial fission through directly phosphorylating AMPKα at S496 by AKT or PKA, resulting in the impairment of AMPK-MFF-DRP1 signaling and mitochondrial dynamics and activity. Since there are significantly increased AMPKα1 phosphorylation at S496 in the liver of elderly mice, obese mice, and obese patients, we, therefore, designed AMPK-specific targeting peptides (Pa496m and Pa496h) to block AMPKα1S496 phosphorylation and found that these targeting peptides can increase AMPK kinase activity, augment mitochondrial fission and oxidation, and reduce ROS, leading to the rejuvenation of mitochondria. Furthermore, these AMPK targeting peptides robustly suppress liver glucose production in obese mice. Our data suggest these targeting peptides are promising therapeutic agents for improving mitochondrial dynamics and activity and alleviating hyperglycemia in elderly and obese patients.

Keywords:  AKT; AMPK targeting peptides; AMPKαS496 phosphorylation; PKA; hyperglycemia; liver gluconeogenesis; mitochondrial fission

DOI:  https://doi.org/10.1016/j.chembiol.2023.09.017
Nat Commun. 2023 Oct 23. 14(1): 6721

The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury.

Hakjoo Lee, Tae Jin Lee, Chad A Galloway, Wenbo Zhi, Wei Xiao, Karen L de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki, Yisang Yoon.

Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

DOI: https://doi.org/10.1038/s41467-023-42564-0
FASEB J. 2023 11;37(11): e23265

Loss of UCP2 causes mitochondrial fragmentation by OMA1-dependent proteolytic processing of OPA1 in podocytes.

Qianqian Yang, Lulu Wang, Yuehong Liang, Qingyu He, Qi Sun, Jing Luo, Hongdi Cao, Yi Fang, Yang Zhou, Junwei Yang, Ping Wen, Lei Jiang.

  Mitochondrial dysfunction plays an important role in the onset and progression of podocyte injury and proteinuria. However, the process by which the change in the podocyte mitochondria occurs is not well understood. Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which is located in the mitochondrial inner membrane. Here, we reported that mice with podocyte-specific Ucp2 deficiency developed podocytopathy with proteinuria with aging. Furthermore, those mice exhibited increased proteinuria in experimental models evoked by Adriamycin. Our findings suggest that UCP2 mediates mitochondrial dysfunction by regulating mitochondrial dynamic balance. Ucp2-deleted podocytes exhibited increased mitochondrial fission and deficient in ATP production. Mechanistically, opacity protein 1 (OPA1), a key protein in fusion of mitochondrial inner membrane, was regulated by UCP2. Ucp2 deficiency promoted proteolysis of OPA1 by activation OMA1 which belongs to mitochondrial inner membrane zinc metalloprotease. Those finding demonstrate the role of UCP2 in mitochondrial dynamics in podocytes and provide new insights into pathogenesis associated with podocyte injury and proteinuria.

Keywords:  OMA1; OPA1; UCP2; mitochondria; podocyte injury

DOI:  https://doi.org/10.1096/fj.202301055R
Biochem Biophys Res Commun. 2023 Oct 15. pii: S0006-291X(23)01200-7. [Epub ahead of print]683 149116

CCDC127 regulates lipid droplet homeostasis by enhancing mitochondria-ER contacts.

Yuchen Xia, Yue Zhang, Yuwei Sun, Li He.

  Lipid droplets (LDs) are both energy storage and signaling organelles playing important roles in various physiological and pathological conditions. The mitochondria-ER contacts have been implicated in regulating the homeostasis of lipid droplets. However, our knowledge about the molecular mechanism behind this regulation is still limited. In this study, we identified CCDC127, a previously uncharacterized protein, as a new regulator of LDs by enhancing the mitochondria-ER contact sites (MERCS). Knockdown and overexpression of CCDC127 in HeLa cells significantly change the LDs abundance in opposite directions, suggesting that CCDC127 positively regulates the LDs. Additional analysis showed that CCDC127 localizes on the outer membrane of mitochondria through its N-terminus and promotes mitochondria fragmentation. Importantly, knockdown or overexpression of CCDC127 significantly down- or up-regulates, respectively, the formation of MERCS. Further experiments showed that CCDC127 is required to stabilize the MERCS tether protein VAPA. And overexpression or knockdown of VAPA reversed the effects of CCDC127 reduction or overexpression on LDs. Finally, we demonstrated that knocking down CCDC127 in the mesenchymal stem cells reduced their differentiation towards adipocytes. These findings provide a new molecular connection between LD homeostasis and MERCS regulation.

Keywords:  CCDC127; Lipid droplet; Mitochondria-ER contact

DOI:  https://doi.org/10.1016/j.bbrc.2023.10.048
Cell Mol Biol Lett. 2023 Oct 27. 28(1): 87

Cadmium promotes nonalcoholic fatty liver disease by inhibiting intercellular mitochondrial transfer.

Jian Sun, Yan Chen, Tao Wang, Waseem Ali, Yonggang Ma, Yan Yuan, Jianhong Gu, Jianchun Bian, Zongping Liu, Hui Zou.

  Mitochondrial transfer regulates intercellular communication, and mitochondria regulate cell metabolism and cell survival. However, the role and mechanism of mitochondrial transfer in Cd-induced nonalcoholic fatty liver disease (NAFLD) are unclear. The present study shows that mitochondria can be transferred between hepatocytes via microtubule-dependent tunneling nanotubes. After Cd treatment, mitochondria exhibit perinuclear aggregation in hepatocytes and blocked intercellular mitochondrial transfer. The different movement directions of mitochondria depend on their interaction with different motor proteins. The results show that Cd destroys the mitochondria-kinesin interaction, thus inhibiting mitochondrial transfer. Moreover, Cd increases the interaction of P62 with Dynactin1, promotes negative mitochondrial transport, and increases intracellular lipid accumulation. Mitochondria and hepatocyte co-culture significantly reduced Cd damage to hepatocytes and lipid accumulation. Thus, Cd blocks intercellular mitochondrial transfer by disrupting the microtubule system, inhibiting mitochondrial positive transport, and promoting their negative transport, thereby promoting the development of NAFLD.

Keywords:  Cadmium; Intercellular mitochondrial transfer; Nonalcoholic fatty liver disease; Tunneling nanotubes

DOI:  https://doi.org/10.1186/s11658-023-00498-x
Nat Commun. 2023 Oct 23. 14(1): 6729

Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.

Hongming Su, Hong Guo, Xiaoxue Qiu, Te-Yueh Lin, Chao Qin, Gail Celio, Peter Yong, Mark Senders, Xianlin Han, David A Bernlohr, Xiaoli Chen.

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.

DOI: https://doi.org/10.1038/s41467-023-42473-2
Sci Rep. 2023 10 24. 13(1): 18129

Disrupted brain mitochondrial morphology after in vivo hydrogen sulfide exposure.

Wilson K Rumbeiha, Dong-Suk Kim, Angela Min, Maya Nair, Cecilia Giulivi.

Changes in mitochondrial dynamics are often associated with dietary patterns, medical treatments, xenobiotics, and diseases. Toxic exposures to hydrogen sulfide (H2S) harm mitochondria by inhibiting Complex IV and via other mechanisms. However, changes in mitochondrial dynamics, including morphology following acute exposure to H2S, are not yet fully understood. This study followed mitochondrial morphology changes over time after a single acute LCt50 dose of H2S by examining electron microscopy thalami images of surviving mice. Our findings revealed that within the initial 48 h after H2S exposure, mitochondrial morphology was impaired by H2S, supported by the disruption and scarcity of the cristae, which are required to enhance the surface area for ATP production. At the 72-h mark point, a spectrum of morphological cellular changes was observed, and the disordered mitochondrial network, accompanied by the probable disruption of mitophagy, was tied to changes in mitochondrial shape. In summary, this study sheds light on how acute exposure to high levels of H2S triggers alterations in mitochondrial shape and structure as early as 24 h that become more evident at 72 h post-exposure. These findings underscore the impact of H2S on mitochondrial function and overall cellular health.

DOI: https://doi.org/10.1038/s41598-023-44807-y
Proc Natl Acad Sci U S A. 2023 Oct 31. 120(44): e2313010120

Misregulation of mitochondria-lysosome contact dynamics in Charcot-Marie-Tooth Type 2B disease Rab7 mutant sensory peripheral neurons.

Yvette C Wong, Nirupa D Jayaraj, Tayler B Belton, George C Shum, Hannah E Ball, Dongjun Ren, Abigail L D Tadenev, Dimitri Krainc, Robert W Burgess, Daniela M Menichella.

  Inter-organelle contact sites between mitochondria and lysosomes mediate the crosstalk and bidirectional regulation of their dynamics in health and disease. However, mitochondria-lysosome contact sites and their misregulation have not been investigated in peripheral sensory neurons. Charcot-Marie-Tooth type 2B disease is an autosomal dominant axonal neuropathy affecting peripheral sensory neurons caused by mutations in the GTPase Rab7. Using live super-resolution and confocal time-lapse microscopy, we showed that mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral sensory neurons. Interestingly, Charcot-Marie-Tooth type 2B mutant Rab7 led to prolonged mitochondria-lysosome contact site tethering preferentially in the axons of peripheral sensory neurons, due to impaired Rab7 GTP hydrolysis-mediated contact site untethering. We further generated a Charcot-Marie-Tooth type 2B mutant Rab7 knock-in mouse model which exhibited prolonged axonal mitochondria-lysosome contact site tethering and defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis as well as fragmented mitochondria in the axon of the sciatic nerve. Importantly, mutant Rab7 mice further demonstrated preferential sensory behavioral abnormalities and neuropathy, highlighting an important role for mutant Rab7 in driving degeneration of peripheral sensory neurons. Together, this study identifies an important role for mitochondria-lysosome contact sites in the pathogenesis of peripheral neuropathy.

Keywords:  Charcot–Marie–Tooth disease; inter-organelle contact site; lysosome; mitochondria; peripheral neuropathy

DOI:  https://doi.org/10.1073/pnas.2313010120
bioRxiv. 2023 Oct 02. pii: 2023.09.29.560159. [Epub ahead of print]

Regulation of astrocyte metabolism by mitochondrial translocator protein 18kDa.

Wyn Firth, Josephine L Robb, Daisy Stewart, Katherine R Pye, Rosemary Bamford, Asami Oguro-Ando, Craig Beall, Kate Lj Ellacott.

The mitochondrial translocator protein 18kDa (TSPO) has been linked to a variety of functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in the periphery using Leydig cells and hepatocytes, as well as work in microglia, indicate that the function of TSPO may vary between cells depending on their specialised roles. Astrocytes are critical for providing trophic and metabolic support in the brain as part of their role in maintaining brain homeostasis. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. However, relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO-deficient (TSPO -/- ) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed metabolic flux analyses. We found that loss of TSPO reduced basal astrocyte respiration and increased the bioenergetic response to glucose reintroduction following glucopenia, while increasing fatty acid oxidation (FAO). Lactate production was significantly reduced in TSPO -/- astrocytes. Co-immunoprecipitation studies in U373 cells revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a, which presents a mechanism wherein TSPO may regulate FAO in astrocytes. Compared to TSPO +/+ cells, inflammation induced by 3h lipopolysaccharide (LPS) stimulation of TSPO -/- MPAs revealed attenuated tumour necrosis factor release, which was enhanced in TSPO -/- MPAs at 24h LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility in astrocytes, loss of TSPO does not appear to modulate the metabolic response of astrocytes to inflammation, at least in response to the stimulus/time course used in this study.

DOI: https://doi.org/10.1101/2023.09.29.560159
Cancer Gene Ther. 2023 Oct 27.

LAMC2 mitigates ER stress by enhancing ER-mitochondria interaction via binding to MYH9 and MYH10.

Dongdong Tong, Jun Zhou, Jing Zhou, Xiaofei Wang, Beibei Gao, Xiaoyi Rui, Liying Liu, QiaoYi Chen, Chen Huang.

Highly proliferative and metastatic tumors are constantly exposed to both intrinsic and extrinsic factors that induce adaptation to stressful conditions. Chronic adaptation to endoplasmic reticulum (ER) ER stress is common to many different types of cancers, and poses a major challenge for acquired drug resistance. Here we report that LAMC2, an extracellular matrix protein upregulated in many types of cancers, is localized in the ER of lung, breast, and liver cancer cells. Under tunicamycin-induced ER stress, protein level of LAMC2 is upregulated. Transfection of cancer cells with LAMC2 resulted in the attenuation of ER stress phenotype, accompanied by elevation in mitochondrial membrane potential as well as reduction in reactive oxygen species (ROS) levels and apoptosis. In addition, LAMC2 forms protein complexes with MYH9 and MYH10 to promote mitochondrial aggregation and increased ER-mitochondria interaction at the perinuclear region. Moreover, overexpression of LAMC2 counteracts the effects of ER stress and promotes tumor growth in vivo. Taken together, our results revealed that in complex with MYH9 and MYH10, LAMC2 is essential for promoting ER-mitochondria interaction to alleviate ER stress and allow cancer cells to adapt and proliferate under stressful conditions. This study provides new insights and highlights the promising potential of LAMC2 as a therapeutic target for cancer treatment.

DOI: https://doi.org/10.1038/s41417-023-00680-5
bioRxiv. 2023 Oct 04. pii: 2023.10.03.560745. [Epub ahead of print]

A DRP-like pseudoenzyme coordinates with MICOS to promote cristae architecture.

Abhishek Kumar, Mehmet Oguz Gok, Kailey N Nguyen, Michael L Reese, Jeremy G Wideman, Sergio A Muñoz-Gómez, Jonathan R Friedman.

Mitochondrial cristae architecture is crucial for optimal respiratory function of the organelle. Cristae shape is maintained in part by the mitochondrial inner membrane-localized MICOS complex. While MICOS is required for normal cristae morphology, the precise mechanistic role of each of the seven human MICOS subunits, and how the complex coordinates with other cristae shaping factors, has not been fully determined. Here, we examine the MICOS complex in Schizosaccharomyces pombe , a minimal model whose genome only encodes for four core subunits. Using an unbiased proteomics approach, we identify a poorly characterized inner mitochondrial membrane protein that interacts with MICOS and is required to maintain cristae morphology, which we name Mmc1. We demonstrate that Mmc1 works in concert with MICOS complexes to promote normal mitochondrial morphology and respiratory function. Bioinformatic analyses reveal that Mmc1 is a distant relative of the Dynamin-Related Protein (DRP) family of GTPases, which are well established to shape and remodel membranes. We find that, like DRPs, Mmc1 self-associates and forms high molecular weight assemblies. Interestingly, however, Mmc1 is a pseudoenzyme that lacks key residues required for GTP binding and hydrolysis, suggesting it does not dynamically remodel membranes. These data are consistent with a model in which Mmc1 stabilizes cristae architecture by acting as a scaffold to support cristae ultrastructure on the matrix side of the inner membrane. Our study reveals a new class of proteins that evolved early in fungal phylogeny and is required for the maintenance of cristae architecture. This highlights the possibility that functionally analogous proteins work with MICOS to establish cristae morphology in metazoans.

DOI: https://doi.org/10.1101/2023.10.03.560745
Aging (Albany NY). 2023 Oct 20. undefined

Poor communication between ER and mitochondria: a signature of ALS/FTD?

Christopher C J Miller, Patricia Gomez-Suaga.



Keywords:  C9orf72; ER-mitochondria signalling; amyotrophic lateral sclerosis; dipeptide repeat polypeptides; frontotemporal dementia

DOI:  https://doi.org/10.18632/aging.205206
Cell Signal. 2023 Oct 21. pii: S0898-6568(23)00354-6. [Epub ahead of print] 110939

FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

Chong Xu, Bin Wang, Mei Li, ZhiFeng Dong, Nan Chen, Junying Duan, Ye Zhou, Mingfeng Jin, Rui Chen, Wei Yuan.

  Mitochondrial dysfunction in pulmonary artery endothelial cells (PAECs) is related to the pathogenesis of pulmonary hypertension (PH). The mitochondrial receptor protein FUN14 domain containing 1 (FUNDC1) was found to be involved in pulmonary artery smooth muscle cell proliferation in PH. However, its role in PAECs remains unclear. We investigated FUNDC1 expression in the pulmonary artery endothelium in both monocrotaline-induced animal models and TNF-α-stimulated cell models. Additionally, the effect of FUNDC1 on PAECs proliferation and its possible mechanism were also investigated. We observed decreased FUNDC1 protein levels in animals and in vitro in PAECs. FUNDC1 deficiency in PAECs upregulated the expression of the deubiquitination enzyme ubiquitin-specific peptidase 15 (USP15), enhanced dynamin-related protein1 (Drp1)-mediated mitochondrial division, and increased mitochondrial ROS levels via the deubiquitination of Drp1. Additionally, FUNDC1 deficiency increased aerobic glycolysis, the production of ATP and lactic acid, and glucose uptake. FUNDC1 overexpression inhibited PAECs proliferation. Moreover, FUNDC1 overexpression in combination with a mitochondrial division or aerobic glycolysis inhibitor enhanced its inhibitory effect on cell proliferation. Our study findings suggest that FUNDC1 deficiency induced by inflammation can promote PAECs proliferation by regulating mitochondrial dynamics and cell energy metabolism via the USP15/Drp1 pathway.

Keywords:  FUNDC1; Mitochondrial; Pulmonary artery endothelial cells; TNF-α

DOI:  https://doi.org/10.1016/j.cellsig.2023.110939