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Item Reconstruction of gene innovation associated with major evolutionary transitions in the kingdom Fungi(BioMed Central Ltd, 2022-12) Wu B; Hao W; Cox MPBACKGROUND: Fungi exhibit astonishing diversity with multiple major phenotypic transitions over the kingdom's evolutionary history. As part of this process, fungi developed hyphae, adapted to land environments (terrestrialization), and innovated their sexual structures. These changes also helped fungi establish ecological relationships with other organisms (animals and plants), but the genomic basis of these changes remains largely unknown. RESULTS: By systematically analyzing 304 genomes from all major fungal groups, together with a broad range of eukaryotic outgroups, we have identified 188 novel orthogroups associated with major changes during the evolution of fungi. Functional annotations suggest that many of these orthogroups were involved in the formation of key trait innovations in extant fungi and are functionally connected. These innovations include components for cell wall formation, functioning of the spindle pole body, polarisome formation, hyphal growth, and mating group signaling. Innovation of mitochondria-localized proteins occurred widely during fungal transitions, indicating their previously unrecognized importance. We also find that prokaryote-derived horizontal gene transfer provided a small source of evolutionary novelty with such genes involved in key metabolic pathways. CONCLUSIONS: The overall picture is one of a relatively small number of novel genes appearing at major evolutionary transitions in the phylogeny of fungi, with most arising de novo and horizontal gene transfer providing only a small additional source of evolutionary novelty. Our findings contribute to an increasingly detailed portrait of the gene families that define fungal phyla and underpin core features of extant fungi.Item Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities(Springer Nature Limited, 2019-12-20) Migliavacca E; Tay SKH; Patel HP; Sonntag T; Civiletto G; McFarlane C; Forrester T; Barton SJ; Leow MK; Antoun E; Charpagne A; Seng Chong Y; Descombes P; Feng L; Francis-Emmanuel P; Garratt ES; Giner MP; Green CO; Karaz S; Kothandaraman N; Marquis J; Metairon S; Moco S; Nelson G; Ngo S; Pleasants T; Raymond F; Sayer AA; Ming Sim C; Slater-Jefferies J; Syddall HE; Fang Tan P; Titcombe P; Vaz C; Westbury LD; Wong G; Yonghui W; Cooper C; Sheppard A; Godfrey KM; Lillycrop KA; Karnani N; Feige JNThe causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD+ levels through perturbed NAD+ biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.Item Historical translocations by Māori may explain the distribution and genetic structure of a threatened surf clam in Aotearoa (New Zealand)(Springer Nature Ltd, 2018-11-22) Ross PM; Knox MA; Smith S; Smith H; Williams J; Hogg IDThe population genetic structure of toheroa (Paphies ventricosa), an Aotearoa (New Zealand) endemic surf clam, was assessed to determine levels of inter-population connectivity and test hypotheses regarding life history, habitat distribution and connectivity in coastal vs. estuarine taxa. Ninety-eight toheroa from populations across the length of New Zealand were sequenced for the mitochondrial cytochrome c oxidase I gene with analyses suggesting a population genetic structure unique among New Zealand marine invertebrates. Toheroa genetic diversity was high in Te Ika-a Māui (the North Island of New Zealand) but completely lacking in the south of Te Waipounamu (the South Island), an indication of recent isolation. Changes in habitat availability, long distance dispersal events or translocation of toheroa to southern New Zealand by Māori could explain the observed geographic distribution of toheroa and their genetic diversity. Given that early-Māori and their ancestors, were adept at food cultivation and relocation, the toheroa translocation hypothesis is plausible and may explain the disjointed modern distribution of this species. Translocation would also explain the limited success in restoring what may in some cases be ecologically isolated populations located outside their natural distributions and preferred nichesItem Effects of Whey Protein on Skeletal Muscle Microvascular and Mitochondrial Plasticity Following 10-Weeks of Exercise Training in Men with Type-2 Diabetes(Canadian Science Publishing, 2021-08) Gaffney K; Lucero A; Macartney-Coxson D; Clapham J; Whitfield P; Palmer BR; Wakefield S; Faulkner J; Stoner L; Rowlands DSAbstract Skeletal muscle microvascular dysfunction and mitochondrial rarefaction feature in type 2 diabetes mellitus (T2DM) linked to low tissue glucose disposal rate (GDR). Exercise training and milk protein supplementation independently promote microvascular and metabolic plasticity in muscle associated with improved nutrient delivery, but combined effects are unknown. In a randomised-controlled trial, 24 men (55.6 y, SD 5.7) with T2DM ingested whey protein drinks (protein/carbohydrate/fat: 20/10/3 g; WHEY) or placebo (carbohydrate/fat: 30/3 g; CON) before/after 45 mixed-mode intense exercise sessions over 10 weeks, to study effects on insulin-stimulated (hyperinsulinemic clamp) skeletal-muscle microvascular blood flow (mBF) and perfusion (near-infrared spectroscopy), and histological, genetic, and biochemical markers (biopsy) of microvascular and mitochondrial plasticity. WHEY enhanced insulin-stimulated perfusion (WHEY-CON 5.6%; 90% CI −0.1, 11.3), while mBF was not altered (3.5%; −17.5, 24.5); perfusion, but not mBF, associated (regression) with increased GDR. Exercise training increased mitochondrial (range of means: 40%–90%) and lipid density (20%–30%), enzyme activity (20%–70%), capillary:fibre ratio (∼25%), and lowered systolic (∼4%) and diastolic (4%–5%) blood pressure, but without WHEY effects. WHEY dampened PGC1α −2.9% (90% compatibility interval: −5.7, −0.2) and NOS3 −6.4% (−1.4, −0.2) expression, but other messenger RNA (mRNA) were unclear. Skeletal muscle microvascular and mitochondrial exercise adaptations were not accentuated by whey protein ingestion in men with T2DM. ANZCTR Registration Number: ACTRN12614001197628. Novelty: • Chronic whey ingestion in T2DM with exercise altered expression of several mitochondrial and angiogenic mRNA. • Whey added no additional benefit to muscle microvascular or mitochondrial adaptations to exercise. • Insulin-stimulated perfusion increased with whey but was without impact on glucose disposal. Résumé Le dysfonctionnement microvasculaire du muscle squelettique et la raréfaction mitochondriale caractérisant le diabète de type 2 (« T2DM ») sont liés à un faible taux d’élimination du glucose tissulaire (« GDR »). L’entraînement physique et la supplémentation en protéines du lait favorisent indépendamment la plasticité microvasculaire et métabolique dans le muscle; cette plasticité est associée à une amélioration de l’apport de nutriments, mais les effets combinés sont inconnus. Dans un essai contrôlé randomisé, 24 hommes (55,6 ans, SD 5,7) aux prises avec le T2DM consomment des boissons protéinées de lactosérum (protéines / glucides / lipides: 20/10/3 g; « WHEY ») ou un placebo (glucides / lipides: 30/3 g; « CON ») avant / après 45 séances d’exercice intense en mode mixte sur 10 semaines, et ce, pour examiner les effets sur le flux sanguin microvasculaire (« mBF ») et la perfusion (spectroscopie proche infrarouge) stimulés par l’insuline (clamp hyperinsulinémique), des variables histologiques, génétiques et des marqueurs biochimiques (biopsie) de la plasticité microvasculaire et mitochondriale. WHEY améliore la perfusion stimulée par l’insuline (WHEY-CON 5,6 %; IC 90 % −0,1, 11,3), tandis que le mBF n’est pas modifié (3,5 %; −17,5, 24,5); la perfusion, mais pas le mBF, est associée (régression) à une augmentation du GDR. L’entraînement à l’exercice augmente la densité mitochondriale (gamme de moyennes: 40-90 %) et lipidique (20−30 %), l’activité enzymatique (20−70 %), le ratio capillaire: fibre (∼25 %) et diminue les pressions systolique (∼4 %) et diastolique (4−5 %), mais sans effets de WHEY. WHEY amortit l’expression de PGC1α −2,9 % (intervalle de compatibilité de 90 % : −5,7, −0,2) et NOS3 −6,4 % (−1,4, −0,2), mais les autres ARN messager (ARNm) ne sont pas clairs. Les adaptations microvasculaires et mitochondriales des muscles squelettiques causées par l’entraînement physique ne sont pas accentuées par la consommation de protéines de lactosérum chez les hommes aux prises avec le T2DM. Numéro d’enregistrement ANXCTR : ACTRN12614001197628. [Traduit par la Rédaction] Les nouveautés: • La consommation prolongée de lactosérum en présence de T2DM combinée à l’entraînement physique modifie l’expression de plusieurs ARNm mitochondriaux et angiogéniques. • Le lactosérum n’ajoute aucun avantage supplémentaire aux adaptations microvasculaires ou mitochondriales musculaires à l’exercice physique. • La perfusion stimulée par l’insuline augmente avec le lactosérum mais n’a pas d’impact sur l’élimination du glucose.Item The effect of manganese on mammalian mitochondria : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, New Zealand(Massey University, 1999) Taylor, Nicolas LyndonManganese (Mn) is an essential trace element, but excessive inhalation can cause serious disorders of the central nervous system, lungs and liver, and results in the condition known as manganism. The general population is exposed to Mn through its use in the fungicide Maneb and MMT, which is used as an anti-knock agent to replaced lead in petrol. Also there have been a number of reports of Mn contaminated drinking water. Victims of Mn poisoning suffer from serious neurological disorders, such as an intermittent tremor of small amplitude, speech impairments and disruption of postural reflexes, which are caused by damage to certain regions of the brain. After prolonged exposure severe symptoms develop that generally resemble those associated with Parkinson's disease. The action of Mn on the brain is not well understood, although three possible mechanisms have been proposed: 1. Inhibition of the mitochondrial electron transfer chain following Mn accumulation by mitochondria. 2. Neuronal degradation by free radicals such as O2 and OH causing lipid peroxidation and damage to DNA and protein. 3. Induction of mutation of the mitochondrial genome, as has previously been shown in both eukaryotes and prokaryoles. It has been shown in this study that Mn inhibits the mitochondrial electron transfer chain. An overall ionic strength inhibition of the entire electron transfer chain was observed, probably mediated by an interference of the electrostatic interactions between cytochrome c and the cytochrome bc1 complex or cytochrome oxidase. Also a direct inhibition of succinate dehydrogenase, NADH dehydrogenase and cytochrome oxidase was observed. This inhibition would be associated with a decrease the production of ATP and could be sufficient to cause the degradation of brain tissue seen in victims of Mn poisoning. It seems likely that if Mn can inhibit the mitochondrial electron transfer chain, this inhibition would lead to an increase in the generation of free radical species by the mitochondria. However, this was not shown in this work, due to difficulties with detector molecules. It was observed that sheep liver mitochondria can oxidise and reduce acetylated cytochrome c, which may not have been previously reported. The effect of Mn on isolated mtDNA showed a decrease in the intensity of PCR products after exposure to Mn, which may have been cause by an interference of the activity of Taq polymerase. It has previously been shown that Mn interferes with the activity of both Taq polymerase and chicken liver mitochondrial polymerase-γ and, if it could interfere with the activity of mitochondrial DNA polymerase, this would also decrease further both the number of functional mitochondria and the production of ATP. A decrease in the production of ATP by mitochondria, or a decrease in the production of functional mitochondria, would lead to cellular death of affected cells and could provide an explanation of the symptoms observed in victims of Mn poisoning.Item The oxidation of linoleate and other long-chain fatty acids in rat and sheep liver mitochondria : a thesis presented in partial fulfilment of the requirement for the degree of Doctor of Philosophy in Biochemistry at Massey University, New Zealand(Massey University, 1986) Reid, John Campbell WilliamSheep liver mitochondria oxidised palmitate, oleate and linoleate at slower rates than did rat liver mitochondria. Rat liver mitochondria oxidised linoleate at 1.2 to 1.7 times the rate observed with palmitates as the substrate. However, sheep liver mitochondria oxidised linoleate at 0.74 to 0.84 the rate observed when palmitate was the substrate. The biochemical basis of this difference is not understood. The reaction catalysed by the enzyme carnitine acyltransferase I is believed to be an important regulatory step in the oxidation of long-chain fatty acids and is known to be competitively inhibited by malonyl-CoA . Both rat and sheep liver mitochondria were able to form acyl carnitine when palmitoyl-CoA and linoleate, coupled with anacyl-CoA generating system, were the acyl substrates. Malonyl-CoA was very effective in inhibiting the CAT I reaction in sheep liver mitochondria. When linoleate, coupled with an acyl-CoA generating system, was the substrate for CAT I, 1uM malonyl-CoA was found to inhibit the reaction by 90%. However, when the same substrate was assayed in rat liver mitochondria the inhibition was much less, 22 uM malonyl-CoA leading to only 50% inhibition of the CAT I enzyme. When palmitoyl-CoA was used as a substrate for the enzyme CAT I, little difference was seen between rat and sheep liver mitochondria in the extent of inhibition observed over the concentration range of 1 to 5 uM malonyl-CoA. These experiments indicate that sheep liver mitochondria could oxidise palmitate rather than linoleate at low levels of malonyl-CoA as one might expect in vivo. In contrast, in rat liver mitochondria, linoleate would be oxidised faster than palmitate at all concentrations of malonyl-CoA investigated. It is suggested that this system may be an important means whereby sheep are able to conserve linoleate by preventing its oxidation. In addition the mitochondrial glycerol3-phosphate acyltransferase reaction was investigated with both sheep and rat liver mitochondria. With linoleate and anacyl-CoA generating system, rat liver preparations esterified 1.5 nmoles min/mg protein whereas sheep liver mitochondria esterified less than one tenth of this. It was concluded esterification of linoleate to glycerol 3-phosphate is not an important mechanism of conserving linoleate in sheep liver mitochondria. Esterification of palmitate to glycerol 3-phosphate was studied using palmitoyl-CoA as the acyl donor. At maximal rates of esterification it was observed that rat liver mitochondria esterified palmitoyl-CoA at 2 nmo les/mi n/mg whereas sheep mi tochondr i a e s ter i f i ed 0 . 8 nmo l e s /mi n/mg .Item Loss of Drosophila Coq8 results in impaired survival, locomotor deficits and photoreceptor degeneration(BioMed Central, 9/02/2022) Hura A; Hannah H; Tan WJ; Penny R; Jessie J; Fitzsimons HCoenzyme Q8A encodes the homologue of yeast coq8, an ATPase that is required for the biosynthesis of Coenzyme Q10, an essential component of the electron transport chain. Mutations in COQ8A in humans result in CoQ10 deficiency, the clinical features of which include early-onset cerebellar ataxia, seizures and intellectual disability. The rapid advancement of massively parallel sequencing has resulted in the identification of more than 40 new mutations in COQ8A and functional studies are required to confirm causality and to further research into determining the specific mechanisms through which the mutations result in loss of function. To that end, a Drosophila model of Coq8 deficiency was developed and characterized to determine its appropriateness as a model system to further explore the role of Coq8 in the brain, and for functional characterisation of Coq8 mutations. Pan-neuronal RNAi knockdown of Coq8 was largely lethal, with female escapers displaying severe locomotor deficits. Knockdown of Coq8 in the eye resulted in degeneration of photoreceptors, progressive necrosis and increased generation of reactive oxygen species. Reintroduction of wild-type Coq8 restored normal function, however expression of human wild-type COQ8A exacerbated the eye phenotype, suggesting it was acting as a dominant-negative. This model is therefore informative for investigating the function of Drosophila Coq8, however human COQ8A mutations cannot be assessed as hCOQ8A does not rescue Coq8 deficiency.