Sepsis-induced mitochondrial dysfunction: A narrative review

Table 1 Different methods of mensuration of mitochondrial damage and recovery

Item	Description
Mitochondrial biogenesis	PPAR-γ coactivator 1-α, nuclear respiratory factor 1, mitochondrial transcription factor A. Material obtained from tissue biopsy or from peripheral PBMC
Mitochondrial content	Mitochondrial mass, concentration and area
Mitochondrial DNA content	PGC-1α, NRF-1, absolute DNA number of copies
Mitochondrial fusion	Mitofusins 1 and 2, optic atrophy 1 protein
Mitochondrial fission	Dynamin-related protein 1 and fission 1 protein

PPAR-γ: Peroxisome proliferator-activated receptor gamma; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha; NRF-1: Nuclear respiratory factor-1; PBMC: Peripheral blood mononuclear cells.

Table 2 Studies that explored association of mitochondrial dysfunction and prognosis in sepsis

Ref.	n of critically ill septic patients	Mitochondrial measurement	Main findings (survivors vs nonsurvivors)
Belikova et al[66], 2007
Brealey et al[18], 2003	28	ATP concentration, Complex I, II, and IV activities in biopsied muscle cells	Sepsis survivors had an increased level of ATP and Complex I and IV activity
Carré et al[35], 2010	16	Mitochondrial morphology (surface density and volume), RT-PCR of mitochondrial biogenesis factors and concentration of Complex I and Complex IV mitochondrial proteins and OXPHOS transcripts in muscle biopsy specimens	Nonsurvivors had an increased decline in mitochondrial surface density, with a similar mitochondrial volume in these groups; OXPHOS transcripts were more abundant in survivors; increased ATP content in survivors; no difference between groups in Complex I and Complex IV activity
Kraft et al[16], 2019	37	qRT-PCR for genes that regulate mitochondrial biogenesis in PBMCs	Increased genetic activation of mitochondrial biogenesis in day 3 compared with day 1; decrease in mtDNA in septic patients compared with controls, with a recovery on day 5; early activation of mitochondrial biogenesis by day 1 associated with ICU discharge; increased mRNA levels in survivors
Japiassú et al[73], 2011	20	Respirometry of PBMC evaluating state 3, 4 and respiratory control ratio	No difference in ADP-stimulated respiration in nonsurvivors, when compared with survivors
Nedel et al[14], 2021	90 patients	Respirometry of permeabilized lymphocytes	Improvement in Complex I, Complex II, basal and in BCE in day 3, compared with day 1, were associated with lower mortality. In multivariate analysis, BCE improvement was associated with lower 6-mo mortality
Puskarich et al[77], 2015	28 patients	Respirometry of platelets	Routine and state 3 respiration were significantly higher in non-survivors compared to survivors; state 4 respiration had a non-significant increase in non-survivors
Pyle et al[55], 2010	Not reported (147 patients, including septic)	mtDNA content from mononuclear cells	No relationship between mtDNA content and survival outcome at 180 d
Sjövall et al[61], 2010	18 patients	Respirometry of isolated platelets evaluating Complex I, state 3, 4 and respiratory control ratio	Non-survivors had an increased Complex I, Complex II, state 3 respiration and an increased respiratory control ratio at day 6-7 of sepsis when compared with survivors
Sjövall et al[82], 2013	20 patients	Respirometry of permeabilized peripheral blood immune cells	Survivors and non-survivors at 90 d after sepsis did not have difference in Complex I plus Complex II respiration normalized to citrate synthase, mtDNA, and cytochrome c

ATP: Adenosine triphosphate; BCE: Biochemical coupling efficiency; ICU: Intensive care unit; qRT-PCR: Quantitative reverse transcriptase-polymerase chain reaction; mtDNA: Mitochondrion desoxyribonucleic acid; OXPHOS: Oxidative phosphorylation; PBMC: Peripheral blood mononuclear cells; ADP: Adenosine diphosphtate.