bims-mevinf 2024-09-01 papers

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

Cell. 2024 Aug 22. pii: S0092-8674(24)00826-2. [Epub ahead of print]187(17): 4549-4551

OLAH connects fatty acid metabolism to the severity of respiratory viral disease.

Rohan Palanki, Hannah Yamagata, Michael J Mitchell.

Respiratory virus infections may cause profound respiratory illness, yet the factors that underlie disease severity are not well understood. In this issue of Cell, Jia, Crawford, et al.1 identify the role of oleoyl-ACP-hydrolase (OLAH) in mediating life-threatening inflammation associated with viral respiratory disease severity.

DOI: https://doi.org/10.1016/j.cell.2024.07.032

Vet Sci. 2024 Aug 15. pii: 376. [Epub ahead of print]11(8):

Transcriptomic Analysis of Metformin's Effect on Bovine Viral Diarrhea Virus Infection.

Zeyu Li, Yuanxiu He, Junzhen Chen, Duoliang Ran, Jianbo Yue, Qiang Fu, Huijun Shi.

(1) Background: Bovine viral diarrhea virus (BVDV) causes calf diarrhea, bovine respiratory syndrome, and cow abortion, resulting in substantial economic losses in the cattle industry. Owing to its persistent infection mechanism, BVDV is a major challenge in the treatment of cattle. (2) Methods: To determine how metformin (Met) inhibits the interaction between BVDV and host cells, we treated BVDV-infected cells with Met. We then performed an RNA sequencing (RNA-seq) analysis of Met-treated cells infected with BVDV to identify differentially expressed genes (DEGs). Consequently, the RNA-seq results were validated through real-time quantitative PCR (qPCR). (3) Results: Our analysis revealed 3169 DEGs in the Met-treated cells (Met group) vs. the negative controls (NC group) and 2510 DEGs in the BVDV-infected cells after pretreatment with Met (MetBVDV group) vs. the BVDV-infected cells (BVDV group). The DEGs were involved in MDBK interactions during BVDV infection, as indicated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The potential interactions of the DEGs were confirmed via a protein-protein interaction (PPI) network. Met treatment induced autophagy signaling activity and the expression of the autophagy-related genes ATG2A, ATG4B, ATG10, and ATG12 in BVDV-infected Met-pretreated cells. (4) Conclusions: We found that the host transcriptomic profile was affected by BVDV infection and Met pretreatment. These findings offer valuable new insights and provide support for future studies on the inhibition of BVDV replication by Met.

Keywords: RNA-seq; bovine viral diarrhea virus; transcriptome analysis

DOI: https://doi.org/10.3390/vetsci11080376

Curr Issues Mol Biol. 2024 Aug 14. 46(8): 8852-8873

ROS Chronicles in HIV Infection: Genesis of Oxidative Stress, Associated Pathologies, and Therapeutic Strategies.

R Harshithkumar, Prachibahen Shah, Pratiksha Jadaun, Anupam Mukherjee.

Reactive oxygen species (ROS) are widely regarded as signaling molecules and play essential roles in various cellular processes, but when present in excess, they can lead to oxidative stress (OS). Growing evidence suggests that the OS plays a critical role in the pathogenesis of HIV infection and is associated with several comorbidities in HIV-infected individuals. ROS, generated both naturally during mitochondrial oxidative metabolism and as a response to various cellular processes, can trigger host antiviral responses but can also promote viral replication. While the multifaceted roles of ROS in HIV pathophysiology clearly need more investigation, this review paper unravels the mechanisms of OS generation in the context of HIV infections, offering insights into HIV viral protein-mediated and antiretroviral therapy-generated OS. Though the viral protein Tat is significantly attributed to the endogenous cellular increase in ROS post HIV infection, this paper sums up the contribution of other viral proteins in HIV-mediated elicitation of ROS. Given the investigations recognizing the significant role of ROS in the onset and progression of diverse pathologies, the paper also explores the critical function of ROS in the mediation of an of array of pathologies associated with HIV infection and retroviral therapy. HIV patients are observed with disruption to the antioxidant defense system, the antioxidant therapy is gaining focus as a potential therapeutic intervention and is well discussed. While ROS play a significant role in the HIV scenario, further exploratory studies are imperative to identifying alternative therapeutic strategies that could mitigate the toxicities and pathologies associated with ART-induced OS.

Keywords: HIV associated dementia; HIV infection; OS; ROS; Tat; antioxidant therapies; antiretroviral therapy; pathogenesis

DOI: https://doi.org/10.3390/cimb46080523

World J Gastroenterol. 2024 Aug 21. 30(31): 3705-3716

Hepatic angiotensin-converting enzyme 2 expression in metabolic dysfunction-associated steatotic liver disease and in patients with fatal COVID-19.

Angus K Jacobs, Steven D Morley, Kay Samuel, Katie Morgan, Lyndsey Boswell, Timothy J Kendall, David A Dorward, Jonathan A Fallowfield, Peter C Hayes, John N Plevris.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), characterised by hepatic lipid accumulation, causes inflammation and oxidative stress accompanied by cell damage and fibrosis. Liver injury (LI) is also frequently reported in patients hospitalised with coronavirus disease 2019 (COVID-19), while pre-existing MASLD increases the risk of LI and the development of COVID-19-associated cholangiopathy. Mechanisms of injury at the cellular level remain unclear, but it may be significant that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes COVID-19, uses angiotensin-converting expression enzyme 2 (ACE2), a key regulator of the 'anti-inflammatory' arm of the renin-angiotensin system, for viral attachment and host cell invasion.
AIM: To determine if hepatic ACE2 levels are altered during progression of MASLD and in patients who died with severe COVID-19.
METHODS: ACE2 protein levels and localisation, and histological fibrosis and lipid droplet accumulation as markers of MASLD were determined in formalin-fixed liver tissue sections across the MASLD pathological spectrum (isolated hepatocellular steatosis, metabolic dysfunction-associated steatohepatitis (MASH) +/- fibrosis, end-stage cirrhosis) and in post-mortem tissues from patients who had died with severe COVID-19, using ACE2 immunohistochemistry and haematoxylin and eosin and picrosirius red staining of total collagen and lipid droplet areas, followed by quantification using machine learning-based image pixel classifiers.
RESULTS: ACE2 staining is primarily intracellular and concentrated in the cytoplasm of centrilobular hepatocytes and apical membranes of bile duct cholangiocytes. Strikingly, ACE2 protein levels are elevated in non-fibrotic MASH compared to healthy controls but not in the progression to MASH with fibrosis and in cirrhosis. ACE2 protein levels and histological fibrosis are not associated, but ACE2 and liver lipid droplet content are significantly correlated across the MASLD spectrum. Hepatic ACE2 levels are also increased in COVID-19 patients, especially those showing evidence of LI, but are not correlated with the presence of SARS-CoV-2 virus in the liver. However, there is a clear association between the hepatic lipid droplet content and the presence of the virus, suggesting a possible functional link.
CONCLUSION: Hepatic ACE2 levels were elevated in nonfibrotic MASH and COVID-19 patients with LI, while lipid accumulation may promote intra-hepatic SARS-CoV-2 replication, accelerating MASLD progression and COVID-19-mediated liver damage.

Keywords: Angiotensin-converting enzyme 2; COVID-19; COVID-19-associated cholangiopathy; Immunohistochemistry; Metabolic dysfunction-associated steatotic liver disease

DOI: https://doi.org/10.3748/wjg.v30.i31.3705