McKenna 2017 MiPschool Obergurgl
Event: MiPschool Obergurgl 2017
A growing body of experimental evidence suggests that mitochondrial function is modified early in critical illness and that dysfunction is related to clinical outcomes [1,2]. Defining and measuring mitochondrial function in a clinical context is challenging. Traditionally, studies assessing the relationship between mitochondrial function and clinical outcomes in critically ill patients have been limited to snapshot quantification of the content or activity of mitochondrial components in frozen tissues but static markers do not reflect the integrated and dynamic function of these complex intracellular organelles, which is influenced by their structural relationships and biochemical environment within the cell. Respirometry offers an alternative approach to exploring integrated mitochondrial function in a dynamic way, through measurements of oxygen consumption rates in fresh tissue or cells . A search of the MEDLINE and PubMed databases (1960 to August 2016) and a manual review of reference lists were conducted to find experimental studies using respirometry in samples extracted from critically ill patients. This search thus yielded six studies. Cohorts included patients in both early (< 48 hours) and late phases of critical illness. Cell types analysed included platelets, peripheral blood mononuclear cells and skeletal muscle. Experimental protocols used intact and permeabilised cells, and various sequences of substrate, inhibitor and uncoupler titrations (SUIT) to generate different respiratory states. Respirometry indices measured in critically ill patient cohorts were compared to controls, and between different timepoints during critical illness. In order to characterise aspects of mitochondrial phenotype associated with clinical outcomes, respiratory indices were compared in survivors and non-survivors, and assessed for correlation with markers of disease severity and organ failure. These functional indices were also expressed relative to putative markers of mitochondrial content (such as mitochondrial DNA, citrate synthase activity and cytochrome c). In the limited number of studies using the technique in critically ill patients, there was significant heterogeneity in the study design, cell type, isolation procedures, experimental conditions (temperature, respiratory media and oxygen concentration), experimental protocols and specific indices of mitochondrial function generated (as well as the nomenclature used to describe them), and quality control procedures. Use of the technique in this context would benefit from standardised protocols and terminology to aid comparison between studies.
Labels: MiParea: Respiration, mt-Medicine, Patients
Event: D1, Oral
- McKenna HT(1,2,3), Martin DS (1,2,3), Murray AJ (2,4)
- Div Surgery Interventional Science, Univ College London
- Centre Altitude Space Extreme Environment Medicine, Inst Sport Exercise Health,
- Royal Free Hospital Intensive Care Unit,
- Dept Physiol, Development Neuroscience,
- Univ Cambridge. - firstname.lastname@example.org
References and support
- Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219-23.
- Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, Stotz M, Singer M (2010) Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med 182:745-51.
- Pesta D, Gnaiger E (2012) High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol 810:25-58.
- Selected mentor:' Pablo M Garcia-Roves