bims-cesemi 2024-10-06 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024‒10‒06
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor

Correction for Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
Human Salivary Histatin 1 Regulating IP3R1/GRP75/VDAC1 Mediated Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAMs) Inhibits Cell Senescence For Diabetic Wound Repair.
Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
Mechanisms of Senescence and Anti-Senescence Strategies in the Skin.
Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.
Dual regulation of IP3 receptors by IP3 and PIP2 controls the transition from local to global Ca2+ signals.
Shikonin ameliorated LPS-induced acute lung injury in mice via modulating MCU-mediated mitochondrial Ca2+ and macrophage polarization.
ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.
Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss.
Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.

Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2418618121

Correction for Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.

DOI: https://doi.org/10.1073/pnas.2418618121
Free Radic Biol Med. 2024 Sep 27. pii: S0891-5849(24)00693-2. [Epub ahead of print]

Human Salivary Histatin 1 Regulating IP3R1/GRP75/VDAC1 Mediated Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAMs) Inhibits Cell Senescence For Diabetic Wound Repair.

Tinghui Xian, Yi Liu, Yongsheng Ye, Bohua Peng, Jie Huang, Lin Liang, Jiaqing Zhang, Hao Wu, Zhen Lin.

  RATIONALE: Difficulty in skin wound healing is a concern for diabetic patients across the world. Impaired mitochondrial dysfunction and aging-related vascular dysfunction in human umbilical vein endothelial cells (HUVECs) caused by oxidative stress are major impediments to diabetic wound healing. However, research on skin repair at the mechanistic level by improving mitochondrial function and inhibiting oxidative stress-induced HUVEC senescence remains lacking.METHODS AND RESULTS: Human saliva effectively inhibits the natural aging of HUVECs through immunodepletion experiments. Histatin 1 (Hst1), a short peptide comprising 38 amino acids, is the primary component of human saliva that prevents HUVEC aging. Based on in vitro findings, Hst1 decreased staining for senescence-associated β-galactosidase activity and expression of mediators of senescence signaling, including p53, p21, and p16. Mechanistically, HUVEC senescence is associated with Hst1-modulated nuclear factor Nrf2 signaling as Hst1 induces ERK-mediated Nrf2 nuclear translocation through NADPH oxidase-dependent ROS regulation, reinforced Nrf2 antioxidant response, and suppressed oxidative stress. RNA sequencing identified that the mitochondrial-related gene set was enriched in the Hst1 group. Coimmunoprecipitation indicated that Hst1 delayed hydrogen peroxide-induced HUVEC senescence by inhibiting mitochondria-associated endoplasmic reticulum (ER) membrane formation mediated by inositol 1,4,5-trisphosphate receptor 1-glucose-regulated protein 75-voltage-dependent anion channel 1 (VDAC1) complex interactions. Furthermore, in aging HUVECs, Hst1 treatment or VDAC1 silencing with small interfering RNA hindered calcium (Ca2+) transfer from the ER to the mitochondria, thereby ameliorating mitochondrial Ca2+ overload and restoring mitochondrial function. In an in vivo mouse model of diabetes mellitus skin defects, Hst1 facilitated wound healing by stimulating the new blood vessel formation and impeding the expression of senescent biomarkers.
CONCLUSIONS: This study proposes a theoretical solution that Hst1 can restore mitochondrial function by inhibiting oxidative stress or cellular senescence, thereby promoting angiogenesis and diabetic wound repair.

Keywords:  Cell senescence; Hst1; IP3R1/GRP75/VDAC1 complex; Mitochondria-associated ER membranes; Mitochondrial function; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.046
Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794

Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.

Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.

  Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.

Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis

DOI:  https://doi.org/10.1016/j.celrep.2024.114794
Biology (Basel). 2024 Aug 23. pii: 647. [Epub ahead of print]13(9):

Mechanisms of Senescence and Anti-Senescence Strategies in the Skin.

Evangelia Konstantinou, Eliane Longange, Gürkan Kaya.

  The skin is the layer of tissue that covers the largest part of the body in vertebrates, and its main function is to act as a protective barrier against external environmental factors, such as microorganisms, ultraviolet light and mechanical damage. Due to its important function, investigating the factors that lead to skin aging and age-related diseases, as well as understanding the biology of this process, is of high importance. Indeed, it has been reported that several external and internal stressors contribute to skin aging, similar to the aging of other tissues. Moreover, during aging, senescent cells accumulate in the skin and express senescence-associated factors, which act in a paracrine manner on neighboring healthy cells and tissues. In this review, we will present the factors that lead to skin aging and cellular senescence, as well as ways to study senescence in vitro and in vivo. We will further discuss the adverse effects of the accumulation of chronic senescent cells and therapeutic agents and tools to selectively target and eliminate them.

Keywords:  SASP; cellular senescence; p16INK4a; senolytics; senomorphics; senotherapy; skin aging

DOI:  https://doi.org/10.3390/biology13090647
Int J Mol Sci. 2024 Sep 13. pii: 9892. [Epub ahead of print]25(18):

Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.

Mikhail V Dubinin, Anastasia E Stepanova, Irina B Mikheeva, Anastasia D Igoshkina, Alena A Cherepanova, Eugeny Yu Talanov, Ekaterina I Khoroshavina, Konstantin N Belosludtsev.

  Duchenne muscular dystrophy is secondarily accompanied by Ca2+ excess in muscle fibers. Part of the Ca2+ accumulates in the mitochondria, contributing to the development of mitochondrial dysfunction and degeneration of muscles. In this work, we assessed the effect of intraperitoneal administration of rhodacyanine MKT077 (5 mg/kg/day), which is able to suppress glucose-regulated protein 75 (GRP75)-mediated Ca2+ transfer from the sarcoplasmic reticulum (SR) to mitochondria, on the Ca2+ overload of skeletal muscle mitochondria in dystrophin-deficient mdx mice and the concomitant mitochondrial dysfunction contributing to muscle pathology. MKT077 prevented Ca2+ overload of quadriceps mitochondria in mdx mice, reduced the intensity of oxidative stress, and improved mitochondrial ultrastructure, but had no effect on impaired oxidative phosphorylation. MKT077 eliminated quadriceps calcification and reduced the intensity of muscle fiber degeneration, fibrosis level, and normalized grip strength in mdx mice. However, we noted a negative effect of MKT077 on wild-type mice, expressed as a decrease in the efficiency of mitochondrial oxidative phosphorylation, SR stress development, ultrastructural disturbances in the quadriceps, and a reduction in animal endurance in the wire-hanging test. This paper discusses the impact of MKT077 modulation of mitochondrial dysfunction on the development of skeletal muscle pathology in mdx mice.

Keywords:  Duchenne muscular dystrophy; GRP75; MKT077; UPR; calcium; mdx mice; skeletal muscle mitochondria

DOI:  https://doi.org/10.3390/ijms25189892
Mol Cell. 2024 Sep 28. pii: S1097-2765(24)00742-1. [Epub ahead of print]

Dual regulation of IP3 receptors by IP3 and PIP2 controls the transition from local to global Ca2+ signals.

Adelina Ivanova, Peace Atakpa-Adaji, Shanlin Rao, Maria Marti-Solano, Colin W Taylor.

  The spatial organization of inositol 1,4,5-trisphosphate (IP3)-evoked Ca2+ signals underlies their versatility. Low stimulus intensities evoke Ca2+ puffs, localized Ca2+ signals arising from a few IP3 receptors (IP3Rs) within a cluster tethered beneath the plasma membrane. More intense stimulation evokes global Ca2+ signals. Ca2+ signals propagate regeneratively as the Ca2+ released stimulates more IP3Rs. How is this potentially explosive mechanism constrained to allow local Ca2+ signaling? We developed methods that allow IP3 produced after G-protein coupled receptor (GPCR) activation to be intercepted and replaced by flash photolysis of a caged analog of IP3. We find that phosphatidylinositol 4,5-bisphosphate (PIP2) primes IP3Rs to respond by partially occupying their IP3-binding sites. As GPCRs stimulate IP3 formation, they also deplete PIP2, relieving the priming stimulus. Loss of PIP2 resets IP3R sensitivity and delays the transition from local to global Ca2+ signals. Dual regulation of IP3Rs by PIP2 and IP3 through GPCRs controls the transition from local to global Ca2+ signals.

Keywords:  Ca(2+) signaling; GPCR; IP(3) receptor; PIP(2); endoplasmic reticulum; phospholipase C; rapamycin; spatial organization

DOI:  https://doi.org/10.1016/j.molcel.2024.09.009
Phytomedicine. 2024 Sep 12. pii: S0944-7113(24)00700-1. [Epub ahead of print]135 156043

Shikonin ameliorated LPS-induced acute lung injury in mice via modulating MCU-mediated mitochondrial Ca2+ and macrophage polarization.

Huang Bao-Yuan, Lu Shu-Ru, Chen Le-Xin, Bai Liang-Liang, Li Cheng-Cheng, Xu Chun-Qi, Li Ming-Jun, Zeng Jia-Xin, Zhang En-Xin, Zhang Xiao-Jun.

  BACKGROUND: Macrophages play a pivotal role in the development and recovery of acute lung injury (ALI), wherein their phenotypic differentiation and metabolic programming are orchestrated by mitochondria. Specifically, the mitochondrial calcium uniporter (MCU) regulates mitochondrial Ca2+ (mCa2+) uptake and may bridge the metabolic reprogramming and functional regulation of immune cells. However, the precise mechanism on macrophages remains elusive. Shikonin, a natural naphthoquinone, has demonstrated efficacy in mitigating ALI and suppressing glycolysis in macrophages, yet which mechanism remains to be fully elucidated.PURPOSE: This study explored whether Shikonin ameliorated ALI via modulating MCU-mediated mCa2+ and macrophage polarization.
METHODS: This study firstly examined the protective effects of Shikonin on LPS-induced ALI mice, and investigated whether it is depends on macrophage by depleting macrophage using clodronate liposomes. The regulatory effect of Shikonin on macrophage polarization and mitochondrial MCU/Ca2+ signal was testified on RAW264.7 cells, and further validated by knocking-down MCU expression or by using RU360, an MCU inhibitor. Additionally, the crucial role of MCU in the therapeutic effect of Shikonin, along with its regulation on macrophage polarization was validated in mice with LPS-induced ALI under the intervention of RU360.
RESULTS: Shikonin alleviated LPS-induced mice ALI, down-regulated inflammatory cytokines and inhibited the pro-inflammatory polarization of macrophages. Intravenous injection of clodronate liposomes on mice abolished the protective effects of Shikonin on ALI. On RAW264.7 cells, LPS&IFN decreased the protein expression of MCU, while induced pro-inflammatory polarization and glycolytic metabolism. In contrast, Shikonin increased MCU expression, activated MCU-mediated mCa2+ signal, promoted the polarization of macrophages to anti-inflammatory M2 phenotype, and driven a metabolic shift from glycolysis to oxidative phosphorylation. Either knocking-down MCU expression or pharmacological inhibiting MCU by using RU360 mitigated the effects of Shikonin on Raw 264.7 cells. Furthermore, RU360 counteracted the ameliorative effect of Shikonin on ALI mice.
CONCLUSION: The current data showed that Shikonin alleviated LPS-induced mice ALI by activating mitochondrial MCU/mCa2+ signal and regulating macrophage metabolism.

Keywords:  Acute lung injury; Macrophage polarization; Mitochondrial calcium uniporter (MCU); Shikonin

DOI:  https://doi.org/10.1016/j.phymed.2024.156043
Cell Commun Signal. 2024 Sep 30. 22(1): 464

ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.

Ying-Jia Chi, Zhen-Yu Bai, Guang-Li Feng, Xiao-Hong Lai, Yu-Feng Song.

  BACKGROUND: Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver.METHODS: In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments.
RESULTS: The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals.
CONCLUSIONS: The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

Keywords:  Ca2+ Signaling; ER-mitochondria contact sites (MERCs); Hepatic lipogenesis; Ip3r-Grp75-Vdac; Seipin

DOI:  https://doi.org/10.1186/s12964-024-01829-x
Geroscience. 2024 Oct 05.

Deletion of the stress response protein REDD1 prevents sodium iodate-induced RPE damage and photoreceptor loss.

Sandeep M Subrahmanian, Esma I Yerlikaya, Siddharth Sunilkumar, Allyson L Toro, Christopher M McCurry, Stephanie L Grillo, Alistair J Barber, Jeffrey M Sundstrom, Michael D Dennis.

  Age-related macular degeneration (AMD) is a leading cause of blindness in elderly populations, yet the molecular events that initiate the early retinal defects that lead to visual function deficits remain poorly understood. The studies here explored a role for the stress response protein Regulated in Development and DNA damage response 1 (REDD1) in the development of retinal pathology by using the oxidant stressor sodium iodate (NaIO3) to model dry AMD in mice. REDD1 protein abundance was increased in the retinal pigmented epithelium (RPE) and retina of mice administered NaIO3. In wild-type REDD1+/+ mice, reactive oxygen species (ROS) levels were robustly increased in the outer retinal layers 1 day after NaIO3 administration, with focal areas of increased ROS seen throughout the outer retina after 7 days. In contrast with REDD1+/+ mice, ROS levels were blunted in REDD1-/- mice after NaIO3 administration. REDD1 was also required for upregulated expression of pro-inflammatory factors in the RPE/retina and immune cell activation in the outer retina following NaIO3 administration. In REDD1+/+ mice, NaIO3 reduced RPE65 and rhodopsin levels in the RPE and photoreceptor layers, respectively. Unlike REDD1+/+ mice, REDD1-/- mice did not exhibit disrupted RPE integrity, retinal degeneration, or photoreceptor thinning. Overall, REDD1 deletion was sufficient to prevent retinal oxidative stress, RPE damage, immune cell activation, and photoreceptor loss in response to NaIO3. The findings support a potential role for REDD1 in the development of retinal complications in the context of dry AMD.

Keywords:  Aging; DDIT4; RTP801; Retinal pigmented epithelium

DOI:  https://doi.org/10.1007/s11357-024-01362-2
EMBO J. 2024 Oct 04.

Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.

Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.

  Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.

Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00241-y