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1.
Sci Rep ; 9(1): 13898, 2019 09 25.
Article in English | MEDLINE | ID: mdl-31554906

ABSTRACT

Mitochondria provide energy for cellular function. We examine daily changing patterns of mitochondrial function and metabolism in Drosophila in vivo in terms of their complex (I-IV) activity, ATP production, glycolysis, and whole fly respiration in the morning, afternoon and night. Complex activity and respiration showed significant and unexpected variation, peaking in the afternoon. However, ATP levels by contrast are >40% greater in the morning and lowest at night when glycolysis peaks. Complex activity modulation was at the protein level with no evidence for differential transcription over the day. Timing differences between increased ATP production and peaks of complex activity may result from more efficient ATP production early in the day leaving complex activity with spare capacity. Optical stimulation of mitochondria is only possible in the mornings when there is such spare capacity. These results provide first evidence of shifts in cellular energy capacity at the organism level. Understanding their translation may be significant to the chosen timing of energy demanding interventions to improve function and health.


Subject(s)
Drosophila/physiology , Mitochondria/physiology , Adenosine Triphosphate/metabolism , Animals , Drosophila/metabolism , Energy Metabolism/physiology , Glycolysis/physiology , Male , Mitochondria/metabolism , Protein Biosynthesis/physiology , Respiration , Transcription, Genetic/physiology
2.
Sci Rep ; 9(1): 12574, 2019 08 29.
Article in English | MEDLINE | ID: mdl-31467395

ABSTRACT

Photoreceptors have high metabolic demands and age rapidly, undermining visual function. We base our understanding mainly on ageing mice where elevated inflammation, extracellular deposition, including that of amyloid beta, and rod and cone photoreceptor loss occur, but cones are not lost in ageing primate although their function declines, revealing that primate and mouse age differently. We examine ageing primate retinae and show elevated stress but low inflammation. However, aged primates have a >70% reduction in adenosine triphosphate (ATP) and a decrease in cytochrome c oxidase. There is a shift in cone mitochondrial positioning and glycolytic activity increases. Bruch's membrane thickens but unlike in mice, amyloid beta is absent. Hence, reduced ATP may explain cone functional decline in ageing but their retained presence offers the possibility of functional restoration if they can be fuelled appropriately to restore cellular function. This is important because as humans we largely depend on cone function to see and are rarely fully dark adapted. Presence of limited aged inflammation and amyloid beta deposition question some of the therapeutic approaches taken to resolve problems of retinal ageing in humans and the possible lack of success in clinical trials in macular degeneration that have targeted inflammatory agents.


Subject(s)
Aging/physiology , Retina/physiology , Adenosine Triphosphate/biosynthesis , Animals , Bruch Membrane/metabolism , Extracellular Space/metabolism , Mice , Mitochondria/metabolism , Primates , Retina/cytology , Retina/metabolism , Species Specificity , Stress, Physiological
3.
Vis Neurosci ; 36: E007, 2019 01.
Article in English | MEDLINE | ID: mdl-31199213

ABSTRACT

Photoreceptors have high energy demands and densely packed mitochondria through which light passes before phototransduction. Old world primates including humans have three cone photoreceptor types mediating color vision with short (S blue), medium (M green), and long (L red) wavelength sensitivities. However, S-cones are enigmatic. They comprise <10% of the total cone population, their responses saturate early, and they are susceptible in aging and disease. Here, we show that primate S-cones actually have few mitochondria and are fueled by glycolysis, not by mitochondrial respiration. Glycolysis has a limited ability to sustain activity, potentially explaining early S-cone saturation. Mitochondria act as optical filters showing reduced light transmission at 400-450 nm where S-cones are most sensitive (420 nm). This absorbance is likely to arise in a mitochondrial porphyrin that absorbs strongly in the Soret band. Hence, reducing mitochondria will improve S-cone sensitivity but result in increased glycolysis as an alternative energy source, potentially increasing diabetic vulnerability due to restricted glucose access. Further, glycolysis carries a price resulting in premature functional decline as seen in aged S-cones. Soret band absorption may also impact on mitochondrial rich M and L cones by reducing sensitivity at the lower end of their spectral sensitivity range resulting in increased differentiation from S-cone responses. These data add to the list of unique characteristic of S-cones and may also explain aspects of their vulnerability.


Subject(s)
Aging/physiology , Color Vision/physiology , Glycolysis/physiology , Mitochondria/physiology , Retinal Cone Photoreceptor Cells/physiology , Absorption, Physicochemical , Aging/metabolism , Animals , Light , Macaca fascicularis , Mitochondria/metabolism , Retinal Cone Photoreceptor Cells/metabolism
4.
Mar Drugs ; 17(5)2019 May 10.
Article in English | MEDLINE | ID: mdl-31083322

ABSTRACT

Carotenoids are implicated in alleviating ageing and age-related diseases in humans. While data from different carotenoids are mixed in their outcomes, those for 9-cis-ß-carotene indicate general positive effects, although basic data on its biological impact are limited. Here, we show that supplementation with 9-cis-ß-carotene in ageing Drosophila melanogaster improved mitochondrial function in terms of ATP production and whole-body respiration and extended mean lifespan. It also resulted in improved mobility. These data provide a potential biological rational for the beneficial effects of dietary supplementation with 9-cis-ß-carotene. These effects may be based on the maintenance of a sound mitochondrial function.


Subject(s)
Chlorophyceae/chemistry , Drosophila melanogaster/drug effects , Mitochondria/drug effects , beta Carotene/pharmacology , Adenosine Triphosphate/metabolism , Animals , Female , Locomotion/drug effects , Longevity/drug effects , Male , Mitochondria/metabolism , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Stereoisomerism , beta Carotene/chemistry , beta Carotene/isolation & purification
5.
Neurobiol Aging ; 70: 140-147, 2018 10.
Article in English | MEDLINE | ID: mdl-30007163

ABSTRACT

Aging is associated with mitochondrial decline and reduced adenosine triphosphate (ATP) production leading to cellular dysfunction, but this is improved by long-wavelength light absorbed by cytochrome c oxidase, increasing cytochrome c oxidase activity, ATP production and improving metabolism, sensory motor function, and cognition. Yet, the sequence of these events is unknown. We give old flies a single 90-minute 670-nm pulse and measure temporal sequences of changes in respiration, ATP, motor, and cognitive ability. Respiration increased significantly 20 minutes after light initiation and remained elevated for 4 days. Measurable ATP increased at 1 hour, peaking at 3 hours, and then declined rapidly. Respiration improved before ATP increased, which indicates an early ATP sink. Flies explore environments stereotypically, which is lost with aging but is reestablished for 7 hours after light exposure. However, again, there are improvements before there are peaks in ATP production. Improved mobility and cognitive function persist after ATP levels return to normal. Hence, elevated ATP in age may initiate independent signaling mechanisms that result in improvements in aged metabolism and function.


Subject(s)
Adenosine Triphosphate/metabolism , Aging/physiology , Cognition/physiology , Mitochondria/physiology , Respiration , Aging/radiation effects , Animals , Basal Metabolism/radiation effects , Behavior, Animal , Cognition/radiation effects , Drosophila melanogaster , Infrared Rays , Male , Mitochondria/radiation effects , Motor Activity , Respiration/radiation effects
6.
Neurobiol Aging ; 66: 131-137, 2018 06.
Article in English | MEDLINE | ID: mdl-29571001

ABSTRACT

This study explored the effects of long-term photobiomodulation (PBM) on the glial and neuronal organization in the striatum of aged mice. Mice aged 12 months were pretreated with PBM (670 nm) for 20 minutes per day, commencing at 5 months old and continued for 8 months. We had 2 control groups, young at 3 months and aged at 12 months old; these mice received no treatment. Brains were aldehyde-fixed and processed for immunohistochemistry with various glial and neuronal markers. We found a clear reduction in glial cell number, both astrocytes and microglia, in the striatum after PBM in aged mice. By contrast, the number of 2 types of striatal interneurons (parvalbumin+ and encephalopsin+), together with the density of striatal dopaminergic terminals (and their midbrain cell bodies), remained unchanged after such treatment. In summary, our results indicated that long-term PBM had beneficial effects on the aging striatum by reducing glial cell number; and furthermore, that this treatment did not have any deleterious effects on the neurons and terminations in this nucleus.


Subject(s)
Aging/pathology , Basal Ganglia/cytology , Basal Ganglia/pathology , Gliosis/pathology , Gliosis/prevention & control , Low-Level Light Therapy/methods , Neuroglia/pathology , Animals , Cell Count , Male , Mice, Inbred C57BL , Time Factors
7.
Neurobiol Aging ; 60: 34-43, 2017 12.
Article in English | MEDLINE | ID: mdl-28917665

ABSTRACT

Mitochondria play a major role in aging. Over time, mutations accumulate in mitochondrial DNA leading to reduced adenosine triphosphate (ATP) production and increased production of damaging reactive oxygen species. If cells fail to cope, they die. Reduced ATP will result in declining cellular membrane potentials leading to reduced central nervous system function. However, aged mitochondrial function is improved by long wavelength light (670 nm) absorbed by cytochrome c oxidase in mitochondrial respiration. In Drosophila, lifelong 670-nm exposure extends lifespan and improves aged mobility. Here, we ask if improved mitochondrial metabolism can reduce functional senescence in metabolism, sensory, locomotor, and cognitive abilities in old flies exposed to 670 nm daily for 1 week. Exposure significantly increased cytochrome c oxidase activity, whole body energy storage, ATP and mitochondrial DNA content, and reduced reactive oxygen species. Retinal function and memory were also significantly improved to levels found in 2-week-old flies. Mobility improved by 60%. The mode of action is likely related to improved energy homeostasis increasing ATP availability for ionic ATPases critical for maintenance of neuronal membrane potentials. 670-nm light exposure may be a simple route for resolving problems of aging.


Subject(s)
Aging/physiology , Aging/radiation effects , Cognition/physiology , Drosophila melanogaster/physiology , Drosophila melanogaster/radiation effects , Energy Metabolism/radiation effects , Infrared Rays , Mitochondria/metabolism , Mitochondria/radiation effects , Motor Activity/physiology , Visual Acuity/physiology , Adenosine Triphosphate/metabolism , Aging/psychology , Animals , DNA, Mitochondrial/metabolism , DNA, Mitochondrial/radiation effects , Electron Transport Complex IV/metabolism , Electron Transport Complex IV/radiation effects , Membrane Potentials , Memory/physiology , Memory/radiation effects , Reactive Oxygen Species/metabolism , Retina/physiology , Retina/radiation effects
8.
Sci Rep ; 7: 46346, 2017 04 12.
Article in English | MEDLINE | ID: mdl-28402329

ABSTRACT

In old world primates including humans, cone photoreceptors are classified according to their maximal sensitivity at either short (S, blue), middle (M, green) or long (L, red) wavelengths. Colour discrimination studies show that the S-cone pathway is selectively affected by age and disease, and psychophysical models implicate their loss. Photoreceptors have high metabolic demand and are susceptible to age or disease-related losses in oxygen and nutrient supply. Hence 30% of rods are lost over life. While comparable losses are not seen in cones, S-cones comprise less than 10% of the cone population, so significant loss would be undetected in total counts. Here we examine young and aged primate retinae stained to distinguish S from M/L-cones. We show there is no age-related cone loss in either cone type and that S-cones are as regularly distributed in old as young primates. We propose that S-cone metabolism is less flexible than in their M/L counterparts, making them more susceptible to deficits in normal cellular function. Hypoxia is a feature of the ageing retina as extracellular debris accumulates between photoreceptors and their blood supply which likely impacts S-cone function. However, that these cells remain in the ageing retina suggests the potential for functional restoration.


Subject(s)
Aging/physiology , Retina/metabolism , Retinal Cone Photoreceptor Cells/metabolism , Age Factors , Animals , Cell Count , Primates , Retina/physiopathology
9.
Sci Rep ; 6: 20038, 2016 Jan 29.
Article in English | MEDLINE | ID: mdl-26821597

ABSTRACT

Blood monocytes are heterogeneous effector cells of the innate immune system. In circulation these cells are constantly in contact with lipid-rich lipoproteins, yet this interaction is poorly characterised. Our aim was to examine the functional effect of hyperlipidaemia on blood monocytes. In the Ldlr(-/-) mouse monocytes rapidly accumulate cytoplasmic neutral lipid vesicles during hyperlipidaemia. Functional analysis in vivo revealed impaired monocyte chemotaxis towards peritonitis following high fat diet due to retention of monocytes in the greater omentum. In vitro assays using human monocytes confirmed neutral lipid vesicle accumulation after exposure to LDL or VLDL. Neutral lipid accumulation did not inhibit phagocytosis, endothelial adhesion, intravascular crawling and transmigration. However, lipid loading led to a migratory defect towards C5a and disruption of cytoskeletal rearrangement, including an inhibition of RHOA signaling. These data demonstrate distinct effects of hyperlipidaemia on the chemotaxis and cytoskeletal regulation of monocyte subpopulations. These data emphasise the functional consequences of blood monocyte lipid accumulation and reveal important implications for treating inflammation, infection and atherosclerosis in the context of dyslipidaemia.


Subject(s)
Lipid Metabolism/drug effects , Lipoproteins, LDL/pharmacology , Lipoproteins, VLDL/pharmacology , Monocytes/drug effects , Monocytes/metabolism , Animals , Cell Adhesion , Cell Movement/drug effects , Cytoskeleton/metabolism , Humans , Hyperlipidemias/blood , Hyperlipidemias/metabolism , Immunophenotyping , Mice , Mice, Knockout , Monocytes/immunology , Peritonitis/immunology , Peritonitis/metabolism , Peritonitis/pathology , Phagocytosis , Phenotype , Signal Transduction/drug effects , Transendothelial and Transepithelial Migration
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