Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression

Sepsis is characterized by a dysregulated immune response, metabolic derangements and bioenergetic failure. These alterations are closely associated with a profound and persisting mitochondrial dysfunction. This however occurs despite increased expression of the nuclear-encoded transcription factor A (TFAM) that normally supports mitochondrial biogenesis and functional recovery. Since this paradox may relate to an altered intracellular distribution of TFAM in sepsis, we tested the hypothesis that enhanced extramitochondrial TFAM expression does not translate into increased intramitochondrial TFAM abundance. Accordingly, we prospectively analyzed PBMCs both from septic patients (n = 10) and lipopolysaccharide stimulated PBMCs from healthy volunteers (n = 20). Extramitochondrial TFAM protein expression in sepsis patients was 1.8-fold greater compared to controls (p = 0.001), whereas intramitochondrial TFAM abundance was approximate 80% less (p < 0.001). This was accompanied by lower mitochondrial DNA copy numbers (p < 0.001), mtND1 expression (p < 0.001) and cellular ATP content (p < 0.001) in sepsis patients. These findings were mirrored in lipopolysaccharide stimulated PBMCs taken from healthy volunteers. Furthermore, TFAM-TFB2M protein interaction within the human mitochondrial core transcription initiation complex, was 74% lower in septic patients (p < 0.001). In conclusion, our findings, which demonstrate a diminished mitochondrial TFAM abundance in sepsis and endotoxemia, may help to explain the paradox of lacking bioenergetic recovery despite enhanced TFAM expression

Bacterial Porin Disrupts Mitochondrial Membrane Potential and Sensitizes Host Cells to Apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (Delta psi(m)). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of Delta psi(m). The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce Delta psi(m) loss and apoptosis, demonstrating that dissipation of Delta psi(m) is a requirement for cell death caused by neisserial infection

Hsp70 in mitochondrial biogenesis

The family of hsp70 (70 kilodalton heat shock protein) molecular chaperones plays an essential and diverse role in cellular physiology, Hsp70 proteins appear to elicit their effects by interacting with polypeptides that present domains which exhibit non-native conformations at distinct stages during their life in the cell. In this paper we review work pertaining to the functions of hsp70 proteins in chaperoning mitochondrial protein biogenesis. Hsp70 proteins function in protein synthesis, protein translocation across mitochondrial membranes, protein folding and finally the delivery of misfolded proteins to proteolytic enzymes in the mitochondrial matrix

Conventional and CT angiography in children: dosimetry and dose comparisons

Tremendous advances have been made in imaging in children with both congenital and acquired heart disease. These include technical advances in cardiac catheterization and conventional angiography, especially with advancements in interventional procedures, as well as noninvasive imaging with MR and CT angiography. With rapid advances in multidetector CT (MDCT) technology, most recently 64-detector array systems (64-slice MDCT), have come a number of advantages over MR. However, both conventional and CT angiography impart radiation dose to children. Although the presence of radiation exposure to children has long been recognized, it is apparent that our ability to assess this dose, particularly in light of the rapid advancements, has been limited. Traditional methods of dosimetry for both conventional and CT angiography are somewhat cumbersome or involve a potential for substantial uncertainty. Recent developments in dosimetry, including metal oxide semiconductor field effect transistors (MOSFET) and the availability of anthropomorphic, tissue-equivalent phantoms have provided new opportunities for dosimetric assessments. Recent work with this technology in state-of-the-art cardiac angiography suites as well as with MDCT have offered direct comparisons of doses in infants and children undergoing diagnostic cardiac evaluation. It is with these dose data that assessment of risks, and ultimately the assessment of risk-benefit, can be better achieved