bims-mecmid 2021-10-17 papers

Front Cardiovasc Med. 2021 ;8 749756

Role of the Mitochondrial Protein Import Machinery and Protein Processing in Heart Disease.

Mitochondria are essential organelles for cellular energy production, metabolic homeostasis, calcium homeostasis, cell proliferation, and apoptosis. About 99% of mammalian mitochondrial proteins are encoded by the nuclear genome, synthesized as precursors in the cytosol, and imported into mitochondria by mitochondrial protein import machinery. Mitochondrial protein import systems function not only as independent units for protein translocation, but also are deeply integrated into a functional network of mitochondrial bioenergetics, protein quality control, mitochondrial dynamics and morphology, and interaction with other organelles. Mitochondrial protein import deficiency is linked to various diseases, including cardiovascular disease. In this review, we describe an emerging class of protein or genetic variations of components of the mitochondrial import machinery involved in heart disease. The major protein import pathways, including the presequence pathway (TIM23 pathway), the carrier pathway (TIM22 pathway), and the mitochondrial intermembrane space import and assembly machinery, related translocases, proteinases, and chaperones, are discussed here. This review highlights the importance of mitochondrial import machinery in heart disease, which deserves considerable attention, and further studies are urgently needed. Ultimately, this knowledge may be critical for the development of therapeutic strategies in heart disease.

Keywords: CHCHD4 (MIA40); TIM22 complex; TIM23 complex; TOM complex; heart disease; mitochondrial protein import machinery

DOI: https://doi.org/10.3389/fcvm.2021.749756

Cell Death Discov. 2020 Oct 12. 6(1): 102

Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1-Drp1 pathway.

Shuai Yang, Bin Hu, Zongming Wang, Changming Zhang, Haosen Jiao, Zhigang Mao, Liguang Wei, Ji Jia, Jingling Zhao.

Activation of the cannabinoid CB1 receptor induces neuroprotection against brain ischemia/reperfusion injury (IRI); however, the mechanism is still unknown. In this study, we used oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in neuronal cells and middle cerebral artery occlusion (MCAO)-induced brain IRI in rats to mimic ischemic brain injury, and hypothesized that the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) would protect ischemic neurons by inhibiting mitochondrial fission via dynamin-related protein 1 (Drp1). We found that OGD/R injury reduced cell viability and mitochondrial function, increased lactate dehydrogenase (LDH) release, and increased cell apoptosis, and mitochondrial fission. Notably, ACEA significantly abolished the OGD/R-induced neuronal injuries described above. Similarly, ACEA significantly reversed MCAO-induced increases in brain infarct volume, neuronal apoptosis and mitochondrial fission, leading to the recovery of neurological functions. The neuroprotective effects of ACEA were obviously blocked by coadministration of the CB1 receptor antagonist AM251 or by the upregulation of Drp1 expression, indicating that ACEA alleviates brain IRI via the CB1-Drp1 pathway. Our findings suggest that the CB1 receptor links aberrant mitochondrial fission to brain IRI, providing a new therapeutic target for brain IRI treatment.

DOI: https://doi.org/10.1038/s41420-020-00338-3

Int J Mol Sci. 2021 Sep 27. pii: 10410. [Epub ahead of print]22(19):

Psoriasiform Inflammation Is Associated with Mitochondrial Fission/GDAP1L1 Signaling in Macrophages.

Ahmed Alalaiwe, Chi-Yuan Chen, Zi-Yu Chang, Jui-Tai Sung, Shih-Yi Chuang, Jia-You Fang.

While psoriasis is known as a T cell- and dendritic cell-driven skin inflammation disease, macrophages are also reported to play some roles in its development. However, the signaling pathway of activated macrophages contributing to psoriasis is not entirely understood. Thus, we aimed to explore the possible mechanisms of how macrophages initiate and sustain psoriasis. The differentiated THP1 cells, stimulated by imiquimod (IMQ), were utilized as the activated macrophage model. IMQ was also employed to produce psoriasis-like lesions in mice. A transcriptomic assay of macrophages revealed that the expressions of pro-inflammatory mediators and GDAP1L1 were largely increased after an IMQ intervention. The depletion of GDAP1L1 by short hairpin (sh)RNA could inhibit cytokine release by macrophages. GDAP1L1 modulated cytokine production by activating the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways. Besides GDAP1L1, another mitochondrial fission factor, Drp1, translocated from the cytosol to mitochondria after IMQ stimulation, followed by the mitochondrial fragmentation according to the immunofluorescence imaging. Clodronate liposomes were injected into the mice to deplete native macrophages for examining the latter's capacity on IMQ-induced inflammation. The THP1 cells, with or without GDAP1L1 silencing, were then transplanted into the mice to monitor the deposition of macrophages. We found a significant THP1 accumulation in the skin and lymph nodes. The silencing of GDAP1L1 in IMQ-treated animals reduced the psoriasiform severity score from 8 to 2. After depleting GDAP1L1, the THP1 recruitment in the lymph nodes was decreased by 3-fold. The skin histology showed that the GDAP1L1-mediated macrophage activation induced neutrophil chemotaxis and keratinocyte hyperproliferation. Thus, mitochondrial fission can be a target for fighting against psoriatic inflammation.

Keywords: Drp1; GDAP1L1; imiquimod; macrophage; mitochondrial fission; psoriasis

DOI: https://doi.org/10.3390/ijms221910410

Molecules. 2021 Sep 28. pii: 5883. [Epub ahead of print]26(19):

Enhancement of O-GlcNAcylation on Mitochondrial Proteins with 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, Contributes to the Mitochondrial Network, Cellular Bioenergetics and Stress Response in Neuronal Cells under Ischemic-like Conditions.

Hui Xu, Mingzhi Du, Yuntian Shen, Yumin Yang, Fei Ding, Shu Yu.

O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g's neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.

Keywords: 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-b-d-pyranoside; O-GlcNAcylation; cellular bioenergetics; mitochondrial homeostasis; neuroprotection; oxygen glucose deprivation/reoxygenation stress

DOI: https://doi.org/10.3390/molecules26195883

PLoS Pathog. 2021 Oct;17(10): e1009841

Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.

Hiroki Sato, Miho Hoshi, Fusako Ikeda, Tomoko Fujiyuki, Misako Yoneda, Chieko Kai.

In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.

DOI: https://doi.org/10.1371/journal.ppat.1009841