Metabolic Characterisation of Critically Ill Patients: An Observational Study Focusing on Mitochondria

Critical illness is associated with significantly increased risk of morbidity and mortality (Morgan, 2021). Patients are often admitted to the intensive care unit (ICU) with single or multiple organ failure of diverse aetiology (e.g., severe infection, inflammation, trauma). Multi-organ failure is related to cellular and bioenergetic dysfunction caused by hypoxia, hyperoxia and increased oxidative stress and despite organ support measures, the anticipated mortality is high with ~20-50% (Zambon and Vincent, 2008). Despite these negative consequences, therapeutic strategies are limited with nearly all ICU based clinical studies failing to identify treatments that improve clinical outcomes. The heterogeneity within the ICU patients coupled with the lack of phenotypic characterisation has contributed to this poor progress, highlighting the need to comprehensively characterise the ICU phenotype to develop effective interventions that improve clinical outcomes.

Mitochondria have vital functions beyond cellular energy metabolism, including regulating cell death, calcium homeostasis and modulation of the cell cycle. All of these functions have been shown to impact outcomes during critical illness with mitochondria exhibiting structural changes within days of being admitted to ICU (Klawitter et al., 2023). Despite appropriate ICU management with antibiotics, fluids, oxygenation and nutrition, sepsis- associated mortality remains high and this is thought to be due to persistence of inflammation and impaired mitochondrial processes (Supinski et al, 2020). Stressed mitochondria produce higher levels of reactive oxygen species, activating caspases, and triggering cell death. Following mitochondrial death, subsequent lack in ATP production has been suggested to lead to poor clinical outcomes. Mitochondrial death itself leads to poor clinical outcomes and a study in 2013 directly linked higher levels of circulating mtDNA to increased ICU mortality at 28-days post admission (Jameson et al., 2023).

Physical inactivity is strongly associated with alterations in mitochondrial dysfunction and consequently prolonged inactivity in ICU may lead to adverse outcomes. Studies show downregulation of key mitochondrial transcription factors in skeletal muscle even in early stages of critical illness (Klawitter et al., 2023). A recent randomised control trial concluded that there was persistent intramuscular inflammation in critical illness and demonstrated that exercise alone is insufficient to restore muscle function (Jameson et al., 2023). A defining feature of ICU patients is the rapid and substantial loss of muscle (Puthucheary et al., 2023), which significantly increases morbidity and mortality risk (key clinical outcomes of ICU) (Lee et al., 2021).

Associated with ICU induced muscle decline is mitochondrial dysfunction, characterised by reduced mitochondrial content and function (Puthucheary et al., 2018). However, where mitochondrial deficiencies occur (e.g., which complex of the electron transport chain), and thus which element of the mitochondria are best to target therapeutically to improve mitochondrial health remains' elusive. These fundamental questions can be addressed using sophisticated omic-informatic techniques; however, this system biology approach requires interdisciplinary expertise, which has stunted progress. Bridging this gap, the investigators have interdisciplinary expertise in applying advanced computational analysis to human biological samples, permitting the detection of molecular targets to improve muscle mitochondrial health (Deane et al., 2019; Deane et al., 2023; Deane et al., 2021). Thus, using our pipeline, it is possible to identify molecular regulators of, and promising interventional avenues for, improving mitochondrial health in ICU patients.

Monitoring mitochondrial function in patients is a bedside challenge, as it requires muscle biopsies followed by laboursome laboratory processing and analysis. Therefore, there is an unmet need to develop minimally or non-invasive methods to assess mitochondrial function to aid clinical decision-making processes. Addressing this research gap, the investigators have developed a novel isotope labelled non-invasive breath test to evaluate mitochondrial function rapidly and repeatedly, which has been validated in healthy subjects and in patients with non-alcoholic fatty liver disease (Afolabi et al., 2018).