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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

¡Viva la mitochondria!: harnessing yeast mitochondria for chemical production

ABSTRACT The mitochondria, often referred to as the powerhouse of the cell, offer a unique physicochemical environment enriched with a distinct set of enzymes, metabolites and cofactors ready to be exploited for metabolic engineering. In this review, we discuss how the mitochondrion has been engineered in the traditional sense of metabolic engineering or completely bypassed for chemical production. We then describe the more recent approach of harnessing the mitochondria to compartmentalize engineered metabolic pathways, including for the production of alcohols, terpenoids, sterols, organic acids and other valuable products. We explain the different mechanisms by which mitochondrial compartmentalization benefits engineered metabolic pathways to boost chemical production. Finally, we discuss the key challenges that need to be overcome to expand the applicability of mitochondrial engineering and reach the full potential of this emerging field.

Biotechnology & Applied Microbiology↗
DOE OSTI2021

Rhoptry kinase protein 39 (ROP39) is a novel factor that recruits host mitochondria to the parasitophorous vacuole of Toxoplasma gondii

ABSTRACT Most intracellular pathogens replicate in a vacuole to avoid the defense system of the host. A few pathogens recruit host mitochondria around those vacuoles, but the molecules responsible for mitochondrial recruitment remain unidentified. It is only in the apicomplexan parasite Toxoplasma gondii, that mitochondrial association factor 1b (MAF1b) has been identified as an association factor for host mitochondria. Here, we show that rhoptry kinase family protein 39 (ROP39) induces host mitochondrial recruitment in T. gondii. We found that the abundance of ROP39 was increased on host mitochondria extracted from human foreskin fibroblasts (HFFs) infected with T. gondii. ROP39 expressed exogenously in HFFs localized on host mitochondria, indicating that it has the potential to bind to host mitochondria without assistance from other parasite factors. Confocal microscopy revealed that ROP39 colocalized with host mitochondria on the membrane of parasitophorous vacuoles, in which the parasites reside. Moreover, we observed about a 10% reduction in the level of mitochondrial association in rop39-knockout parasites compared with a parental strain.

Fukumoto, Junpei↗
DOE OSTI2021

Dietary vitamin E reaches the mitochondria in the flight muscle of zebra finches but only if they exercise

Whether dietary antioxidants are effective for alleviating oxidative costs associated with energy-demanding life events first requires they are successfully absorbed in the digestive tract and transported to sites associated with reactive species production (e.g. the mitochondria). Flying birds are under high energy and oxidative demands, and although birds commonly ingest dietary antioxidants in the wild, the bioavailability of these consumed antioxidants is poorly understood. We show for the first time that an ingested lipophilic antioxidant, α-tocopherol, reached the mitochondria in the flight muscles of a songbird but only if they regularly exercise (60 min of perch-to-perch flights two times in a day or 8.5 km day -1 ). Deuterated α-tocopherol was found in the blood of exercise-trained zebra finches within 6.5 hrs and in isolated mitochondria from pectoral muscle within 22.5 hrs, but never reached the mitochondria in caged sedentary control birds. This rapid pace (within a day) and extent of metabolic routing of a dietary antioxidant to muscle mitochondria means that daily consumption of such dietary sources can help to pay the inevitable oxidative costs of flight muscle metabolism, but only when combined with regular exercise.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT)

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

A photosensitive sustainable lignin nanoplatform for multimodal image-guided mitochondria-targeted photodynamic and photothermal therapy

Photoactivated nanocarriers exhibit significant potential for anticancer therapy, but complex design strategies, unsustainable substrates, and short wavelengths limit their practical application. Here, we designed a new lignin-derived photoactivated nanomaterial that exploits the sensitivity of the β-O-4 bond of lignin to singlet oxygen. This sustainable product was loaded with mitochondria-targeting chlorin e6 and black phosphorus quantum dots (BPQDs) to produce BPQDs@N-LgC NPs, which were used for mitochondria-targeted fluorescence/photoacoustic-guided photothermal and photodynamic therapy. When irradiated at 808 nm, the BPQDs in BPQDs@N-LgC NPs exhibited good photothermal conversion, which allowed photoacoustic imaging and inhibited tumor growth. When irradiated at 660 nm, the BPQDs@N-LgC NPs generated fluorescence and reactive oxygen species, which allowed photoluminescence imaging and further inhibited tumor growth. Cleavage of the β-O-4 bond of lignin by photo-triggered reactive oxygen species degraded the NPs and released the BPQDs, facilitating rapid excretion of the therapeutic nanomaterials. Our rationally designed BPQDs@N-LgC NPs exhibited good therapeutic efficacy, both in vitro and in vivo.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Structure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria

All kingdoms of life produce essential nicotinamide dinucleotide NADP(H) using NAD kinases (NADKs). A panel of published NADK structures from bacteria, eukaryotic cytosol, and yeast mitochondria revealed similar tetrameric enzymes. Here, we present the 2.8-Å structure of the human mitochondrial kinase NADK2 with a bound substrate, which is an exception to this uniformity, diverging both structurally and biochemically from NADKs. We show that NADK2 harbors a unique tetramer disruptor/dimerization element, which is conserved in mitochondrial kinases of animals (EMKA) and absent from other NADKs. EMKA stabilizes the NADK2 dimer but prevents further NADK2 oligomerization by blocking the tetramerization interface. This structural change bears functional consequences and alters the activation mechanism of the enzyme. Whereas tetrameric NADKs undergo cooperative activation via oligomerization, NADK2 is a constitutively active noncooperative dimer. Thus, our data point to a unique regulation of NADP(H) synthesis in animal mitochondria achieved via structural adaptation of the NADK2 kinase.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Reduced ribonucleotide reductase RRM2 subunit expression increases DNA damage and mitochondria dysfunction in woody breast chickens

Abstract OBJECTIVE The aim of this study was to investigate the roles of ribonucleotide reductase subunit M2 (RRM2; subunit of ribonucleotide reductase) in severe woody breast (WB) and normal breast muscles. ANIMALS 40 8-week-old male Ross-708 broiler chickens. METHODS Quantitative PCR was performed to determine gene expression, and commercial ELISA/assay kits were used to obtain several enzymatic activities. RESULTS Results showed that RRM2 activity (P= .0002) and RRM2 (P= .05) and hydroxymethylbilane synthase expression (impaired oxygen transport and metabolism,P= .002) were reduced in WB, while caveolin-3 (defected membrane integrity,P= .09), endoglin (increased fibrosis,P= .06), and secreted protein acidic rich in cysteine (metabolic dysregulation,P= .09) expression tended to increase in WB. WB tended to have increased levels of homocysteine (P= .06), aspartate aminotransferase mitochondria (P= .02), pyruvate kinase (P= .04), DNA damage (P= .06), creatine kinase (P= .05), and triglyceride (P= .002) but decreased ATPase activity (P= .01), all indicating mitochondria dysfunction and tissue damage. CLINICAL RELEVANCE In this study, differences in various enzyme activities and increased DNA damage suggest that RRM2-mediated mitochondrial abnormalities may play a role in WB myopathy.

Veterinary Sciences↗
DOE OSTI2021

Continuous assessment of metabolic activity of mitochondria using resonance Raman microspectroscopy

Dysfunctional mitochondrial activity can lead to a variety of different diseases. As such, there exists a need to quantify changes in mitochondria function as it relates to these specific diseased states. Here, we present the use of resonance Raman (RR) spectroscopy as a tool to determine changes in isolated mitochondrial activity. RR spectroscopy, using 532 nm as the excitation source, specifically provides information on the reduction and oxidation (RedOx) state of cytochrome c, which is determined by the activity of protein complexes in the electron transport chain. In this model, injection of the substrate succinate into the mitochondrial sample is used to drive the electron transport chain, which causes a subsequent change in cytochrome c RedOx state. This change in RedOx state is tracked by RR spectroscopy. We report this tool gives real-time information on the rise and fall of the amount of reduced cytochrome c within the mitochondrial sample, providing a method for rapid assessment of mitochondrial metabolism that has broad applications in both basic science and medical research.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Elevated nocturnal respiratory rates in the mitochondria of CAM plants: current knowledge and unanswered questions

Abstract Crassulacean acid metabolism (CAM) is a metabolic adaptation that has evolved convergently in 38 plant families to aid survival in water-limited niches. Whilst primarily considered a photosynthetic adaptation, CAM also has substantial consequences for nocturnal respiratory metabolism. Here, we outline the history, current state and future of nocturnal respiration research in CAM plants, with a particular focus on the energetics of nocturnal respiratory oxygen consumption. Throughout the 20th century, research interest in nocturnal respiration occurred alongside initial discoveries of CAM, although the energetic and mechanistic implications of nocturnal oxygen consumption and links to the operation of the CAM cycle were not fully understood. Recent flux balance analysis (FBA) models have provided new insights into the role that mitochondria play in the CAM cycle. Several FBA models have predicted that CAM requires elevated nocturnal respiratory rates, compared to C3 species, to power vacuolar malic acid accumulation. We provide physiological data, from the genus Clusia, to corroborate these modelling predictions, thereby reinforcing the importance of elevated nocturnal respiratory rates for CAM. Finally, we outline five unanswered questions pertaining to nocturnal respiration which must be addressed if we are to fully understand and utilize CAM plants in a hotter, drier world.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Skeletal tissue regulation by catalase overexpression in mitochondria

Accumulation of oxidative damage from excess reactive oxygen species (ROS) may contribute to skeletal aging and mediate adverse responses to physiological challenges. Wild-type (WT) mice and transgenic mice (male, 16 wk of age) with human catalase targeted to the mitochondria (mCAT) were analyzed for skeletal responses to the remodeling stimuli of combined hind-limb unloading and exposure to ionizing radiation ( 137 Cs, 2 Gy). Treatment for 2 wk caused lipid peroxidation in the bones WT but not mCAT mice, showing that transgene expression mitigated oxidative stress. Ex vivo osteoblast colony growth rate was 95% greater in mCAT than WT mice and correlated with catalase activity levels ( P < 0.005, r = 0.67), although terminal osteoblast and osteoclast differentiation were unaffected. mCAT mice had lower cancellous bone volume and cortical size than WT mice. Ambulatory control mCAT animals also displayed reduced cancellous and cortical structural properties compared with control WT mice. In mCAT but not WT mice, treatment caused an unexpectedly rapid radial expansion (+8% cortical area, +22% moment of inertia), reminiscent of compensatory bone growth during advancing age. In contrast, treatment caused similar structural deficits in cancellous tissue of mCAT and WT mice. In sum, mitochondrial ROS signaling via H 2 O 2 was important for the acquisition of adult bone structure and catalase overexpression failed to protect cancellous tissue from treatment. In contrast, catabolic stimuli caused radial expansion in mCAT not WT mice, suggesting that mitochondrial ROS in skeletal cells act to suppress tissue turnover in response to remodeling challenges.

Cell Biology↗