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DNA damage, nucleolar stress and dysregulated energy metabolism as mechanisms of multimorbidity

Lookup NU author(s): Professor Gavin RichardsonORCiD

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This is the final published version of an article that has been published in its final definitive form by medRxiv, 2023.

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Abstract

Background: Two-thirds of people over 65 have two or more underlying chronic conditions. Patients with multimorbidities are likely to classify as frail and have worse outcomes after cardiac surgery. We hypothesized that metabolite and transcript profiles could identify multimorbidity-specific mechanisms for clinical interventions. Methods and Results: The multimorbidity was defined as two or more coexisting chronic conditions. Analysis of the metabolome was performed in 30 sequential patients. Measurements of transcriptome and metabolites involved in energy production were performed in 53 and 57 sequential patients, respectively. Mitochondrial function in circulating monocytes was performed in 63 sequential patients. Our analysis distinguished three major processes that are affected by multimorbidity: innate immune response, DNA damage and associated epigenetic changes, and mitochondrial energy production. The innate immune response was upregulated in multimorbidity and most of the included comorbidities. The DNA damage, epigenetic changes and aspects of mitochondrial function were specific for multimorbidity. Histone 2B, its ubiquitination enzymes and AKT3 were upregulated in the multimorbid group suggesting senescence-like changes in gene expression. That was confirmed by the detection of senescence-associated secretory phenotype analytes, IL-1β, its receptor and fractalkine that increased with the number of accumulating comorbidities. DNA damage was confirmed by independent immunohistochemistry experiments, which also identified nucleolar instability as more prominent in the multimorbid myocardium. The nucleolar stress is potentially responsible for higher expression of ribosomal proteins and decreased mitochondrial function. Conclusions: Our results suggest that accumulating comorbidities increase levels of innate immune response and lead to DNA damage, senescence-like changes in gene expression and consequently decreased mitochondrial function.

Publication metadata

Author(s): Tomkova k, Roman M, Adebayo AS, Sheikh S, Yusoff S, Gulston M, Joel-David L, Lai FY, Murgia A, Eagle-Hemming B, Aujla H, Richardson GD, Griffin JL, Murphy GJ, Wozniak MJ

Publication type: Article

Publication status: Published

Journal: medRxiv

Year: 2023

Online publication date: 24/02/2023

Acceptance date: 24/02/2023

Date deposited: 27/02/2023

ISSN (electronic): 3067-2007

Publisher: medRxiv

URL: https://doi.org/10.1101/2023.02.22.23286318

DOI: 10.1101/2023.02.22.23286318

ePrints DOI: 10.57711/pthj-dx18

Notes: Preprint - not peer-reviewed

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