Brown 2017 MiPschool Obergurgl

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COST Action MitoEAGLE
Peroxisomes; underappreciated sources, including post glucose depletion but prior to ketosis, of mitochondrial energy substrates; medium fats and ACoA? Polyunsaturated fats being preferred peroxisomal substrates; energetic implications of Omega 3:6 imbalances, including for the brain.

Link: MitoEAGLE

Brown RA (2017)

Event: MiPschool Obergurgl 2017

COST Action MitoEAGLE

Mitochondrial and peroxisomal function are inextricably interlinked[1]. Peroxisomes have multiple functions including, as arguable key partners in mitochondrial metabolic and redox function. Consideration here is limited to their role in providing substrate to mitochondria, their impact on redox regulation pathways, and consequences of imbalances in dietary polyunsaturated fat intakes[2].

Human peroxisomes can beta-oxidise a number of substrates including branched chain fats, ‘oxidised’ fats such as LOX COX P450 products, and all fats longer than 8 carbons. The products are peroxide, heat, acyl-CoA, and medium chain fats, which can be fed to mitochondria as fuel, and / or diverted for creation of substrate, including lipids and sterols, to support tissue function and repair. In contrast mitochondria beta-oxidise substrate primarily to energy and related pathways.

Crucially, the preferred peroxisomal substrate appears to be 18 carbon polyunsaturated fats, ranked by number of double bonds, thus; Linolenic acid (ALA)>Gamma linoleic>Linoleic (LA)>Oleic,[3] which is consistent with the plant; ‘origins’ of peroxisomes, and metabolic prominence of 18 carbon polyunsaturated fats, including in photosynthesis and germination. LA and ALA together, due to their dominance in green and plant reproductive material, are the predominant terrestrial fats. Mitochondria oxidise medium chain fats avidly, saturated fats well, and polyunsaturates less well, but synergistically struggle or cannot beta-oxidise longer fats e.g. docosahexaenoic acid that peroxisomes beta-oxidise well. Again synergistically, peroxisomes unlike mitochondria oxidise medium-fats poorly.

They are working in concert; peroxisomes provide medium fats and ACoA to the mitochondria. Both likely bypass the need for carnitine to enter the mitochondria (but not MCAD see below), bypassing the insulin / malonyl-CoA related regulation of entry of fats into the mitochondria (Randle Cycle), providing alternative energy pathways, during glucose shortage and or blockage of entry of long fats, and in situations of glucose pathways dysbiosis e.g. diabetes and Alzheimer’s.

Further peroxisomes impact redox by producing peroxide and catalase. Catalase is the most efficient reducer of peroxide, and catalase production is believed limited or absent from mitochondria. Peroxisomal catalase and peroxide production both likely help regulate mitochondrial redox status. The crucial importance of interaction between peroxisomes and mitochondria is deduced from the metabolic effects of MCAD (medium-chain acyl-coenzyme deficiency disorder): failure to access food containing glucose substrate results in brain damage, even death, in hours, because ‘ketosis’ does not develop in short time frames. However new babies with limited access to glucose in new breast milk, and Inuit with a CPT1A polymorphism inhibiting import of long chain fats into the mitochondria on a native marine fat rich diet, with functioning MCAD, both not in significant ketosis, function perfectly normally, suggesting alternative fuels to glucose or ketones must exist; logically medium fats/ACoA. The peroxisomes are the only available logical endogenous source of these mitochondrial substrates, through peroxisomal beta-oxidation of stored lipid adipose sources including polyunsaturated fats.

Further and synergistically PPAR (peroxisome proliferator alpha) pathways are activated in fasting and exercise, and for both, peroxisomal beta-oxidation is arguably an important energy resource. Peroxisomes proliferation, whilst not as marked as in rodents, is seen in humans and pigs. Interestingly migrating birds, possibly migrating monogastrics, and diving mammals, may utilise stored lipids, particularly polyunsaturated fats, via peroxisomal beta-oxidation for energy. Further, opportunity exists to recycle peroxide through catalase back to oxygen, so improving oxygen efficiency, which would be a useful adaptation at altitude, during flight, or whilst diving.

LA has wider metabolic roles; the oxidation of LA within cardiolipin modulates mitochondrial function, including energy production, ultimately inducing damage[4] and apoptosis. In contrast, but to a lesser degree, Omega 3 ALA uprates PPAR alpha activity, and is preferentially metabolised by peroxisomes compared to Omega 6 LA. Further ALA derivative DHA presence in cardiolipin likely alters energetics, and modulates mitochondrial oxidative pathways including apoptosis.

Interestingly, and arguably with crucial metabolic and wider health consequences, including in western inflammatory, lipid deposition related comorbid non-infective western conditions, the primary activators of PPAR gamma pathways are oxidised products of LA. Thus, excess dietary intake of LA and preoxidised LA, imbalance of LA / ALA, combined with calorific excess, significantly impact, metabolic regulation through manipulation of the peroxisomal metabolic pathways, as well as redox regulation. Peroxisomal product of PPAR gamma activation is likely directed to tissue creation repair and oxidative stress related pathways, directing substrate to repair or energy pathways, promoting inflammation, and intracellular lipid deposition. Significant LA is stored in human adipose tissue.

Alternatively in energy shortage such as during exercise or fasting, PPAR alpha activation enables mitochondrial function via significant peroxisomal supply of substrates ACoA and medium chain fats. Peroxisomes through ACoA, and short chain fat provision, are arguably; central to human energy provision including pre-ketosis, and or repair substrate supply, so ultimately survival, and via astrocytic pathways crucial in fuelling, and for supply of substrate to the brain, the seat of humanity.


Bioblast editor: Kandolf G


Labels: MiParea: Exercise physiology;nutrition;life style 

Stress:Oxidative stress;RONS  Organism: Human 




Event: B1, Oral 


Affiliations

Chair - McCarrison Society, London, UK.- rab5155@gmail.com

References

  1. Ed. Hegde M, Zanwar A, Sharad P (2016) Omega-3 Fatty Acids Keys to Nutritional Health. R Brown 27-32.
  2. Fransen M, Lismont C, Walton P (2017) The Peroxisome-Mitochondria Connection: How and Why? Int J Molec Sc 18:1126.·
  3. Hiltunen J, Kark T, Hassinen I, Osmundsen H (1986) Beta-oxidation of polyunsaturated fatty acids by rat liver peroxisomes. J Biol Chem 261:16484–93.
  4. Ghosh S, Qi D, An D, Pulinilkunnil T, Abrahani A, Kuo K, Wambolt R, Allard M, Innis S, Rodrigues B (2004) Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA. Am J Physiol Heart Circ Physiol 287:H2518–27.