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Mitochondria between nuclear and immune networks: AT A D3mental choice for DNA roads or a Parkin’ lot?

Mitochondria are vital for their role of generating energy and are “dynamic”, meaning they constantly fuse together and split apart. They contain a small amount of genetic information known as mitochondrial DNA (mtDNA). The mtDNA, organized into dot-like structures called “nucleoids”, also moves around inside the mitochondria. The method of distribution of mtDNA remained unclear, but now a research team led by Osaka University has identified a molecule known as ATAD3A that is essential for nucleoid movement and could be a potential therapeutic candidate for mitochondrial diseases. The team had previously shown that the movement of the nucleoids is linked to the fission of mitochondria. However, the mechanisms and function of this movement were unclear. The researchers therefore investigated the role of ATAD3A in nucleoid movement because of its previously established links to nucleoid formation.

In a study published recently in the Proceedings of the National Academy of Sciences, the researchers showed that ATAD3A, which is anchored to the inner mitochondrial membrane, mediated the interaction of mtDNA nucleoids inside the mitochondria, with factors involved in mitochondrial fission (present on the outer mitochondrial membrane). They demonstrated that ATAD3A was essential for the active movement of mtDNA nucleoids within the mitochondria and that nucleoids were abnormally clustered in cells that lack mitochondrial fission. Together, mitochondrial fission and nucleoid trafficking determine the size, number, and distribution of the nucleoids within the mitochondria. The distribution of nucleoids throughout the mitochondrial network activates expression of the mtDNA and increases formation of the “respiratory chain complex”, and the correct distribution of the mtDNA nucleoids is key for efficient energy production.

Therefore, not only does this work increase our knowledge of the regulatory processes in mitochondria but it also provides scope for developing future therapies against abnormal mitochondrial functioning. However, these cellular organelles are required not only for providing energy: Professor Konstanze Winklhofer and her group at the Faculty of Medicine at Ruhr University Bochum, Germany, recently discovered that mitochondria play another important role in signal transduction in innate immune pathways. They regulate a signaling pathway that helps to eliminate pathogens, but can cause damage through inflammation upon overactivation. Certain cytokines but also intracellular pathogens, such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression of various genes. However, upon excessive and prolonged activation, this basically protective pathway can cause chronic inflammation.

The new study has revealed that mitochondria play a crucial role in the regulation of the NF-κB signaling pathway. Within minutes after pathway activation, a signaling platform assembles at the outer mitochondrial membrane, resulting in the activation of NF-κB. This allows signal amplification, based on the large surface of mitochondria. Moreover, these organelles have another capacity that qualifies them for signal transduction: they are mobile and can dock onto motor proteins in the cell. The research team observed that mitochondria escort the activated transcription factor NF-κB to the nuclear membrane, thus facilitating the translocation of NF-κB into the nucleus. However, mitochondria are not only involved in the efficient activation of the NF-κB signaling pathway; they also contribute to its deactivation. This is accomplished by an enzyme located at the outer mitochondrial membrane, called protein-ubiquitin lyase, required for NF-κB activation.

Two genes causally linked to Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signaling pathway: PINK1 and Parkin. Scientists think that these data explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions. Indeed, dopaminergic neurons in Parkinson die as the result for excessive oxidative stress. In addition, the findings show that Parkinson’s disease patients with mutations in the PINK1 or Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, there is a direct connection between mitochondria and immune activation in specific subsets of situation between the nervous and immune systems. Figures that these tiny “ancient leftovers” hold in store more than every scientist ever expected.

  • Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.

Scientific references

Ishihara T et al. PNAS USA 2022 Nov 22; 119(47): in press.

Kocaturk NM et al. Cell Death Dis. 2022 Nov 10; 13(11):947. 

Lawrence GMEP et al. Trends Immunol. 2022 Nov; 43(11):877. 

Takeichi Y et al. Diabetologia. 2021 Sep; 64(9):2092-2107. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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