Mitochondrial dysfunction caused by bacteria activates intrinsic apoptosis and inflammation

Monash Biomedicine Discovery Institute (BDI) scientists have discovered a previously unknown method used by bacteria to evade immune responses.

The study, published in Nature Microbiology, points to potential new ways of countering bacterial infections, which are becoming increasingly resistant to antibiotics.First author Dr Pankaj Deo said researchers in Dr Thomas Naderer’s laboratory took a different approach to understanding the process by which bacteria release toxins that disarm the “powerhouse” mitochondria in immune cells.The study showed that immune cells sense that their mitochondria are no longer functional during infections, which triggers apoptosis. “Ironically, it is the activation of host cell death factors that deliver the final blow to mitochondria which induces apoptosis, not the bacterial toxins themselves,” Dr Pankaj said.The researchers genetically targeted apoptotic factors and showed that they were able to reduce inflammation in mice, which increased health outcomes.They used the bacterial pathogens Neisseria gonorrhoeae, uropathogenic Escherichia coli and the deadly Pseudomonas aeruginosa, prevalent in hospitals and which can be multi-drug resistant. However, the findings would apply to other species of bacteria too, Dr Deo said.Dr Naderer, who oversaw the research, said that understanding the ways some bacterial infections evade immune response by targeting mitochondria opens new therapeutic possibilities.“There’s been a lot of effort trying to block endotoxins that kill immune cells but this study really shifts the focus onto different toxins that might be more important,” Dr Naderer said.“It gives us a few good leads that we can look at as a next step,” he said.“We’ve shown in this paper that we can accelerate the immune response,” he said. “The other side is that if that response persists and we get constant inflammation – which is usually associated with bacterial infection and which causes a lot of tissue damage – we have a new way to shut down that tissue-damaging inflammation.”“What scientists have thought before is that when endotoxins are released by bacteria they induce an inflammatory type of programmed cell death called pyroptosis in immune cells,” Dr Deo said. Endotoxins are part of the external cell wall of essentially all Gram-negative bacteria.“We’ve found that the pathogenic bacteria use a similar mechanism to release additional toxins,” he said. “They kill immune cells by releasing small surface structures called outer membrane vesicles – packages of toxins that target mitochondria. The mitochondria are disarmed, become dysfunctional then die according to apoptosis or cellular suicide.”The scientists will investigate drugs that are now advancing to the clinic, and at repurposing drugs already in use, perhaps as anti-cancer treatments, to see if they can be used to clear bacterial infections.

News source: www.technologynetworks.com

Article: Deo et al. (2020). Mitochondrial dysfunction caused by outer membrane vesicles from Gram-negative bacteria activates intrinsic apoptosis and inflammation. Nature Microbiology. DOI: https://doi.org/10.1038/s41564-020-0773-2

Lack of mitochondria causes severe disease in children

The absence of FBXL4 leads to degradation of mitochondria that results in decreased ATP (energy) production and mitochondrial disease. Credit : news.ki.se

Researchers at Karolinska Institutet have discovered that excessive degradation of the power plants of our cells plays an important role in the onset of mitochondrial disease in children. These inherited metabolic disorders can have severe consequences such as brain dysfunction and neurological impairment. The study is published in EMBO Molecular Medicine.

“This is a completely new disease mechanism for mitochondrial disease which may provide a novel entry point for treating affected patients,” says Nils-Göran Larsson, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, who led the study.

Mitochondrial diseases are inherited metabolic disorders that affect about 1 in 4,300 individuals and are caused by dysfunctional mitochondria. Mitochondria are the power plants of our cells and are crucial for converting energy derived from our food into the energy currency that drives the cell’s biochemical functions. Not surprisingly, organs that are mainly affected in patients are those with a high energy demand, such as the brain, heart, skeletal muscles, eyes and ears. In children, severe multisystem involvement and neurodegeneration are frequent manifestations.

Severe consequences

FBXL4 is a gene that is implicated in controlling mitochondrial function, and mutations in this gene are one of the most common causes of mitochondrial diseases. FBXL4 mutations have been linked to encephalopathy, a form of brain dysfunction causing neurological impairment. The manifestations are impaired cognitive function, developmental regression, epileptic seizures and other types of neurological deficits. Despite the severe consequences of FBXL4 mutations in humans, the function of the protein that FBXL4 codes for has remained poorly understood.

In the current study, researchers generated mice that lack FBXL4 and showed that these mice recapitulate important characteristics present in patients with FBXL4 mutations. They were able to demonstrate that the reduced mitochondrial function is caused by increased degradation of mitochondria via a process called autophagy.

Too few mitochondria in the tissues

In the absence of FBXL4, mitochondria are more frequently delivered to the lysosome, the recycling station of the cell that contains enzymes that break down organic compounds. FBXL4 thus acts as a break on mitochondrial degradation. Patients who lack FBXL4 have too few mitochondria in their tissues which leads to disease.

“Further studies are needed to explore the therapeutic potential of these findings, in particular whether inhibition of the degradation of mitochondria may provide a new treatment strategy,” says Nils-Göran Larsson.

The study was financed by several bodies, including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council, the Swedish Cancer Society, and the ALF agreement between the Swedish government and the regional councils.

News source : https://news.ki.se/lack-of-mitochondria-causes-severe-disease-in-children

Authors : David Alsina, Oleksandr Lytovchenko, Aleksandra Schab, Ilian Atanassov, Florian A Schober, Min Jiang, Camilla Koolmeister, Anna Wedell, Robert W Taylor, Anna Wredenberg, Nils‐Göran Larsson

EMBO Mol Med (2020) 12: e11659https://doi.org/10.15252/emmm.201911659 

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Mitochondrial RNA degradation is essential for life

Credit : pubmed

Researchers at Karolinska Institutet have discovered the essential role of the ribonuclease REXO2 in mitochondrial RNA degradation. The enzyme is essential for life, as a deficiency of it in mice has shown to be embryonic lethal. The study is published in the journal Molecular Cell.