Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives

Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer

LACTB is a relatively unknown mitochondrial protein structurally related to the bacterial penicillin-binding and beta-lactamase superfamily of serine proteases. LACTB has recently gained an increased interest due to its potential role in lipid metabolism and tumorigenesis. To date, around ninety studies pertaining to LACTB have been published, but the exact biochemical and cell biological function of LACTB still remain elusive. In this review, we summarise the current knowledge about LACTB with particular attention to the implications of the recently published study on the cryo-electron microscopy structure of the filamentous form of LACTB. From this and other studies, several specific properties of LACTB emerge, suggesting that the protein has distinct functions in different physiological settings. Resolving these issues by further research may ultimately lead to a unified model of LACTB’s function in cell and organismal physiology. LACTB is the only member of its protein family in higher animals and LACTB may, therefore, be of particular interest for future drug targeting initiatives

Regulation of the Permeability Transition Pore in Skeletal Muscle Mitochondria MODULATION BY ELECTRON FLOW THROUGH THE RESPIRATORY CHAIN COMPLEX I

We have investigated the regulation of the permeability transition pore (PTP), a cyclosporin A-sensitive channel, in rat skeletal muscle mitochondria. As is the case with mitochondria isolated from a variety of sources, skeletal muscle mitochondria can undergo a permeability transition following Ca2+uptake in the presence of Pi. We find that the PTP opening is dramatically affected by the substrates used for energization, in that much lower Ca2+ loads are required when electrons are provided to complex I rather than to complex II or IV. This increased sensitivity of PTP opening does not depend on differences in membrane potential, matrix pH, Ca2+ uptake, oxidation-reduction status of pyridine nucleotides, or production of H2O2, but is directly related to the rate of electron flow through complex I. Indeed, and with complex I substrates only, pore opening can be observed when depolarization is induced with uncoupler (increased electron flow) but not with cyanide (decreased electron flow). Consistent with pore regulation by electron flow, we find that PTP opening is inhibited by ubiquinone 0 at concentrations that partially inhibit respiration and do not depolarize the inner membrane. These data allow identification of a novel site of regulation of the PTP, suggest that complex I may be part of the pore complex, and open new perspectives for its pharmacological modulation in living cells

Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease

Peer reviewe

Novel Mitochondrial Creatine Transport Activity: IMPLICATIONS FOR INTRACELLULAR CREATINE COMPARTMENTS AND BIOENERGETICS

Immunoblotting of isolated mitochondria from rat heart, liver, kidney, and brain with antibodies made against N- and C-terminal peptide sequences of the creatine transporter, together with in situ immunofluorescence staining and immunogold electron microscopy of adult rat myocardium, revealed two highly related polypeptides with molecular masses of ∼70 and ∼55 kDa in mitochondria. These polypeptides were localized by immunoblotting of inner and outer mitochondrial membrane fractions, as well as by immunogold labeling in the mitochondrial inner membrane. In addition, a novel creatine uptake via a mitochondrial creatine transport activity was demonstrated by [14C]creatine uptake studies with isolated mitochondria from rat liver, heart, and kidney showing a saturable low affinity creatine transporter, which was largely inhibited in a concentration-dependent manner by the sulfhydryl-modifying reagent NEM, as well as by the addition of the above anti-creatine transporter antibodies to partially permeabilized mitochondria. Mitochondrial creatine transport was to a significant part dependent on the energetic state of mitochondria and was inhibited by arginine, and to some extent also by lysine, but not by other creatine analogues and related compounds. The existence of an active creatine uptake mechanism in mitochondria indicates that not only creatine kinase isoenzymes, but also creatine transporters and thus a certain proportion of the creatine kinase substrates, might be subcellularly compartmentalized. Our data suggest that mitochondria, shown here to possess creatine transport activity, may harbor such a creatine/phosphocreatine pool

Semi-natural habitats in the European boreal region : Caught in the socio-ecological extinction vortex?

We propose to consider semi-natural habitats-hotspots for biodiversity-being caught in a socio-ecological extinction vortex, similar to the phenomenon described for species threatened with extinction. These habitats are essentially socioecological systems, in which socioeconomic drivers are interlinked with ecological processes. We identify four highly interlinked and mutually reinforcing socio-economic processes, pertaining to the importance of semi-natural habitats for (i) agricultural production, (ii) policy, research and development; (iii) vocational education in the fields of agricultural sciences and (iv) public's experiences with semi-natural habitats. Evidence from six countries in the boreal region demonstrates that recent slowing down or even reversal of two processes are insufficient to stop the extinction vortex phenomenon. We suggest research directions to ascertain the phenomenon, monitor its development and develop proactive actions to weaken the vortex. It is highly plausible that interventions directed at most, if not all, of the key vortex processes are needed to reverse the overall deteriorating trends of a socio-ecological system.Peer reviewe