bims-mikwok 2023-11-26 papers

J Ethnopharmacol. 2023 Nov 18. pii: S0378-8741(23)01241-2. [Epub ahead of print]320 117371

Zishen Tongyang Huoxue decoction (TYHX) alleviates sinoatrial node cell ischemia/reperfusion injury by directing mitochondrial quality control via the VDAC1-β-tubulin signaling axis.

Xing Chang, Siyuan Zhou, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Qin Zhang, Zhiming Liu, Ruxiu Liu.

ETHNOPHARMACOLOGICAL RELEVANCE: Zishen Tongyang Huoxue decoction (TYHX) has been used clinically for nearly 40 years to treat sick sinus syndrome. Previous reports showed that TYHX can inhibit calcium flux by regulating mitochondrial homeostasis via β-tubulin and increase sinoatrial node cell (SNC) activity. However, the underlying mechanisms remain unclear.
AIM OF THE STUDY: We aimed to verify the protective effect of TYHX against SNC ischemia by regulating mitochondrial quality control (MQC) through β-tubulin and voltage-dependent anion-selective channel 1 (VDAC1) silencing.
MATERIALS AND METHODS: We established an in vitro model of SNC ischemia/reperfusion (I/R) injury and performed rescue experiments by silencing β-tubulin and VDAC1 expression. Cell-Counting Kit 8 assays were performed to detect cell viabilities, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays (paired with confocal microscopy) were performed to detect fragmentation. Mitochondrial-energy metabolism was detected using the Seahorse assay system. Reverse transcription-quantitative polymerase chain reaction analysis was performed to detect the mRNA-expression levels of MQC-related genes.
RESULTS: TYHX inhibited SNC mitochondrial injury. During I/R simulation, TYHX maintained β-tubulin stability, regulated synergy between mitophagy and the mitochondrial unfolded-protein response (UPRmt), and inhibited mitochondrial oxidative stress and overactive SNC fission. Next-generation sequencing suggested that mitochondrial-membrane injury caused SNC apoptosis. We also found that TYHX regulated β-tubulin expression through VDAC1 and inhibited dynamin-related protein 1 migration to mitochondria from the nucleus. After preventing excessive mitochondrial fission, the mitophagy-UPRmt pathway, mitochondrial-membrane potential, and mitochondrial energy were restored. VDAC1 silencing affected the regulatory mechanism of MQC in a β-tubulin-dependent manner via TYHX.
CONCLUSION: TYHX regulated mitochondrial membrane-permeability through VDAC1, which affected MQC through β-tubulin and inhibited mitochondrial apoptosis. Our findings may help in developing drugs to protect the sinoatrial node.

Keywords: Sinoatrial node cell; VDAC1; Zishen Tongyang Huoxue decoction; β-tubulin

DOI: https://doi.org/10.1016/j.jep.2023.117371

Poult Sci. 2023 Oct 28. pii: S0032-5791(23)00766-6. [Epub ahead of print]103(1): 103247

Drp1 regulated PINK1-dependent mitophagy protected duck follicular granulosa cells from acute heat stress injury.

Chen Yang, Pei Luo, You-Tian Yang, Xin-Liang Fu, Bing-Xin Li, Xu Shen, Dan-Ning Xu, Yun-Mao Huang, Yun-Bo Tian, Wen-Jun Liu.

The mitochondrial quality control system is crucial in maintaining cellular homeostasis during environmental stress. Granulosa cells are the main cells secreting steroid hormones, and mitochondria are the key organelles for steroid hormone synthesis. The impact of the mitochondrial quality control system on granulosa cells' steroid hormone synthesis and survival under heat stress is still unclear. Here, we showed that acute heat stress induces mitochondrial damage and significantly increases the number of mitophagy-like vesicles in the cytoplasm of duck ovary granulosa cells at the ultra-structural level. Meanwhile, we also found heat stress significantly increased mitochondrial fission and mitophagy-related protein expression levels both in vivo and in vitro. Furthermore, by confocal fluorescence analysis, we discovered that LC3 was distributed spot-like manner near the nucleus in the heat treatment group, and the LC3 spots and lysosomes were colocalized with Mito-Tracker in the heat treatment group. We further detected the mitophagy-related protein in the cytoplasm and mitochondria, respectively. Results showed that the PINK1 protein was significantly increased both in cytoplasm and mitochondria, while the LC3-Ⅱ/LC3-Ⅰ ratio increase only occurred in mitochondrial. In addition, the autophagy protein induced by acute heat treatment was effectively inhibited by the mitophagy inhibitor CysA. Finally, we demonstrated that the alteration of cellular mitophagy by siRNA interference with Drp1 and PINK1 inhibited the steroid synthesis of granulosa cells and increased cell apoptosis. Study provides strong evidence that the Drp1 regulated PINK1-dependent mitophagy pathway protects follicular granulosa cells from acute heat stress-induced injury.

Keywords: Drp1; PINK1; granulosa cells; heat stress; mitophagy

DOI: https://doi.org/10.1016/j.psj.2023.103247

Biochem Soc Trans. 2023 Nov 21. pii: BST20230377. [Epub ahead of print]

Mechanisms of stress management in mitochondrial protein import.

Maryam Mukhtar, Krutika Thakkur, Agnieszka Chacinska, Piotr Bragoszewski.

Mitochondria are vital to the functions of eukaryotic cells. Most mitochondrial proteins are transported into the organelle following their synthesis by cytoplasmic ribosomes. However, precise protein targeting is complex because the two diverse lipid membranes encase mitochondria. Efficient protein translocation across membranes and accurate sorting to specific sub-compartments require the cooperation of multiple factors. Any failure in mitochondrial protein import can disrupt organelle fitness. Proteins intended for mitochondria make up a significant portion of all proteins produced in the cytosol. Therefore, import defects causing their mislocalization can significantly stress cellular protein homeostasis. Recognition of this phenomenon has increased interest in molecular mechanisms that respond to import-related stress and restore proteostasis, which is the focus of this review. Significantly, disruptions in protein homeostasis link strongly to the pathology of several degenerative disorders highly relevant in ageing societies. A comprehensive understanding of protein import quality control will allow harnessing this machinery in therapeutic approaches.

Keywords: mitochondria; protein degradation; protein transport; proteostasis; proteotoxicity; stress

DOI: https://doi.org/10.1042/BST20230377

J Nutr Biochem. 2023 Nov 17. pii: S0955-2863(23)00269-3. [Epub ahead of print] 109536

Vitamin B12-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice.

Ela Mishra, Mahendra Kumar Thakur.

Memory impairment during aging and amnesia is attributed to compromised mitochondrial dynamics and mitophagy and other mitochondrial quality control mechanisms. Mitochondrial dynamics involves the continuous process of fission and fusion of mitochondria within a cell and is a fundamental mechanism for regulating mitochondrial quality and function. An extensive range of potential nutritional supplements has been shown to improve mitochondrial health, synaptic plasticity, and cognitive functions. Previous findings revealed that supplementation of vitamin B12-folic acid reduces locomotor deficits and mitochondrial abnormalities but enhances mitochondrial and neuronal health. The present study aims to explore the impact of combined vitamin B12-folic acid supplementation on mitochondrial dynamics, neuronal health, and memory decline in old age and scopolamine-induced amnesia, which remains elusive. The results demonstrated that supplementation led to a noteworthy increase in recognition and spatial memory and expression of memory-related protein BDNF in old and amnesic mice. Moreover, the decrease in the fragmented mitochondrial number was validated by the downregulation of mitochondrial fission p-Drp1 (S616) protein and the increase in elongated mitochondria by the upregulation of mitochondrial fusion Mfn2 protein. The increased spine density and dendritic arborization in old and amnesic mice upon supplementation were confirmed by the enhanced expression level of PSD95 and synaptophysin. Furthermore, supplementation reduced ROS production, inhibited Caspase-3 activation, mitigated neurodegeneration, and enhanced mitochondrial membrane potential, ATP production, Vdac1 expression, myelination, in old and amnesic mice. Collectively, our findings imply that combined supplementation of vitamin B12-folic acid improves mitochondrial dynamics and neuronal health, and leads to recovery of memory during old age and amnesia.

Keywords: Aging; Amnesia; Memory; Mitochondrial dynamics; Neurodegeneration; Nutritional supplement

DOI: https://doi.org/10.1016/j.jnutbio.2023.109536

Nat Commun. 2023 Nov 22. 14(1): 7636

The heat shock protein LarA activates the Lon protease in response to proteotoxic stress.

Deike J Omnus, Matthias J Fink, Aswathy Kallazhi, Maria Xandri Zaragoza, Axel Leppert, Michael Landreh, Kristina Jonas.

The Lon protease is a highly conserved protein degradation machine that has critical regulatory and protein quality control functions in cells from the three domains of life. Here, we report the discovery of a α-proteobacterial heat shock protein, LarA, that functions as a dedicated Lon regulator. We show that LarA accumulates at the onset of proteotoxic stress and allosterically activates Lon-catalysed degradation of a large group of substrates through a five amino acid sequence at its C-terminus. Further, we find that high levels of LarA cause growth inhibition in a Lon-dependent manner and that Lon-mediated degradation of LarA itself ensures low LarA levels in the absence of stress. We suggest that the temporal LarA-dependent activation of Lon helps to meet an increased proteolysis demand in response to protein unfolding stress. Our study defines a regulatory interaction of a conserved protease with a heat shock protein, serving as a paradigm of how protease activity can be tuned under changing environmental conditions.

DOI: https://doi.org/10.1038/s41467-023-43385-x