Control of Mitochondrial Substrate Oxidation

doi:10.1016/B978-0-12-152510-1.50012-2

Current Topics in Bioenergetics

Volume 10, 1980, Pages 217-278

https://doi.org/10.1016/B978-0-12-152510-1.50012-2 Get rights and content

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This chapter discusses the control of oxidative metabolism by adenosine diphosphate (ADP) availability in isolated mitochondria and perfused organs. It focuses on the control of dehydrogenase activity. The enzymes, such as, the pyruvate dehydrogenase complex and some of the enzymes of the tricarboxylate cycle have been considered. The most important characteristics of these enzymes are that (1) they catalyze non-equilibrium reactions; (2) exert a dominant influence over the flux through the pathways that are central to catabolic metabolism; and (3) they are mitochondrial. This localization means that the supply of substrate, and dissipation of product, might be limited by the permeability properties of the inner mitochondrial membrane. Because these enzymes are dehydrogenases, the final arbiter of their activity is the respiratory chain, with its coupling to the phosphorylation of ADP. The chapter describes the control of the tricarboxylate cycle and of pyruvate dehydrogenase in their mitochondrial context

References (194)

T.P.M. Akerboom et al.
FEBS Lett.
(1977)
G.F. Azzone et al.
Biochim. Biophys. Acta
(1978)
G.F. Azzone et al.
Biochim. Biophys. Acta
(1978)
J.J. Batenburg et al.
Biochem. Biophys. Res. Commun.
(1975)
J.J. Batenburg et al.
J. Biol. Chem.
(1976)
M.D. Brand et al.
J. Biol. Chem.
(1976)
M.D. Brand et al.
FEBS Lett.
(1978)
S. Cha et al.
J. Biol. Chem.
(1964)
B. Chance et al.
J. Biol. Chem.
(1961)
P.K. Chiang et al.
J. Biol. Chem.
(1975)

E.N. Christiansen et al.

Biochim. Biophys. Acta

(1978)

W.A. Coty et al.

J. Biol. Chem.

(1974)

E.J. Davis et al.

Biochem. Biophys. Res. Commun.

(1978)

S.C. Dennis et al.

J. Biol. Chem.

(1979)

R.M. Denton et al.

Int. J. Biochem.

(1978)

J. Duszynski et al.

J. Biol. Chem.

(1978)

J.A. Gimpel et al.

Biochim. Biophys. Acta

(1973)

G.D. Greville

Curr. Top. Bioenerg.

(1969)

R.G. Hansford

FEBS Lett.

(1972)

R.G. Hansford

J. Biol. Chem.

(1976)

R.G. Hansford

J. Biol. Chem.

(1977)

R.G. Hansford

Comp. Biochem. Physiol. B

(1978)

R.G. Hansford et al.

Biochem. Biophys. Res. Commun.

(1967)

R.G. Hansford et al.

Arch. Biochem. Biophys.

(1978)

R.G. Hansford et al.

J. Biol. Chem.

(1975)

I.E. Hassinen et al.

Biochim. Biophys. Acta

(1975)

J.K. Hiltunen et al.

Biochim. Biophys. Acta

(1976)

J.K. Hiltunen et al.

Int. J. Biochem.

(1977)

M. Hirashima et al.

J. Biol. Chem.

(1967)

A. Holian et al.

Arch. Biochem. Biophys.

(1977)

F. Hucho et al.

Arch. Biochem. Biophys.

(1972)

F.E. Hull et al.

J. Mol. Cell. Cardiol.

(1973)

A. Kemp et al.

Biochim. Biophys. Acta

(1969)

G.W. Kosicki et al.

J. Biol. Chem.

(1966)

U. Küster et al.

Biochim. Biophys. Acta

(1976)

K. LaNoue et al.

J. Biol. Chem.

(1970)

K.F. LaNoue et al.

J. Biol. Chem.

(1972)

K.F. LaNoue et al.

J. Biol. Chem.

(1973)

K.F. LaNoue et al.

Arch. Biochem. Biophys.

(1974)

K. LaNoue et al.

J. Biol. Chem.

(1978)

A.L. Lehninger

J. Biol. Chem.

(1946)

A.B. Leiter et al.

J. Biol. Chem.

(1978)

J.J. Lemasters et al.

J. Biol. Chem.

(1979)

E. Lerner et al.

J. Biol. Chem.

(1972)

G. Löffler et al.

FEBS Lett.

(1975)

M. Lopes-Cardozo et al.

Biochim. Biophys. Acta

(1972)

M.J. Achs et al.

Am. J. Physiol.

(1977)

T.P.M. Akerboom et al.

Eur. J. Biochem.

(1978)

P. Borst

Wiss. Konf. Ges. Dtsch. Naturforsch. Aerzte

(1963)

J. Bremer

Eur. J. Biochem.

(1969)

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Citation Excerpt :
ROS generation by the KGDHc is a major source of the mitochondrial oxidative stress (Adam-Vizi and Tretter, 2013; Andreyev et al., 2005, 2015; Mailloux et al., 2016; Quinlan et al., 2014; Rimessi et al., 2016; Shi et al., 2008; Starkov, 2013; Starkov et al., 2004; Tretter and Adam-Vizi, 2004). This, together with the compromised activity of the KGDHc, a key enzyme in the Krebs cycle (Gibson et al., 2000; Hansford, 1980; Lai et al., 1977; Massey, 1960a; Reed, 1974; Sheu and Blass, 1999), is highly implicated in hypoxia- and glutamate-induced cerebral damage, Wernicke-Korsakoff syndrome, neurodegenerative diseases, Friedreich's ataxia, ischemia-reperfusion, progressive supranuclear palsy, senescence/aging, infantile lactate acidosis, cancer, and E3-deficiency, among others (Albers et al., 2000; Anderson et al., 2016; Bunik et al., 2007; Burr et al., 2016; Butterworth and Besnard, 1990; Butterworth et al., 1993; Cameron et al., 2006; Chen et al., 2016; Droge and Schipper, 2007; Gibson et al., 1988, 2000, 2003, 2010; Graf et al., 2009; Klivenyi et al., 2004; Lucas and Szweda, 1999; Mastrogiacomo et al., 1996a, 1996b; Mizuno et al., 1990; Park et al., 2001; Peiris-Pages et al., 2015; Starkov, 2008; Starkov and Adam-Vizi, 2010; Tretter and Adam-Vizi, 2004, 2005; Zundorf et al., 2009). ROS generation by the PDHc appears to be significant only in vitro (Ambrus et al., 2015b; Fisher-Wellman et al., 2013; Mailloux et al., 2016; Quinlan et al., 2014; Starkov et al., 2004).
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Ghost moths (Lepidoptera: Hepialidae) are cold-adapted stenothermal species inhabiting alpine meadows on the Tibetan Plateau. They have an optimal developmental temperature of 12–16 °C but can maintain feeding and growth at 0 °C. Their survival strategies have received little attention, but these insects are a promising model for environmental adaptation. Here, biochemical adaptations and energy metabolism in response to cold were investigated in larvae of the ghost moth Hepialus xiaojinensis. Metabolic rate and respiratory quotient decreased dramatically with decreasing temperature (15–4 °C), suggesting that the energy metabolism of ghost moths, especially glycometabolism, was sensitive to cold. However, the metabolic rate at 4 °C increased with the duration of cold exposure, indicating thermal compensation to sustain energy budgets under cold conditions. Underlying regulation strategies were studied by analyzing metabolic differences between cold-acclimated (4 °C for 48 h) and control larvae (15 °C). In cold-acclimated larvae, the energy generating pathways of carbohydrates, instead of the overall consumption of carbohydrates, was compensated in the fat body by improving the transcription of related enzymes. The mobilization of lipids was also promoted, with higher diacylglycerol, monoacylglycerol and free fatty acid content in hemolymph. These results indicated that cold acclimation induced a reorganization on metabolic structure to prioritise energy metabolism. Within the aerobic process, flux throughout the tricarboxylic acid (TCA) cycle was encouraged in the fat body, and the activity of α-ketoglutarate dehydrogenase was the likely compensation target. Increased mitochondrial cristae density was observed in the midgut of cold-acclimated larvae. The thermal compensation strategies in this ghost moth span the entire process of energy metabolism, including degration of metabolic substrate, TCA cycle and oxidative phosphorylation, and from an energy budget perspective explains how ghost moths sustain physiological activity in cold environments.
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Citation Excerpt :
Obviously, over-production of ROS may lead to cellular damage in any organism or tissue [28–30,36,95]. In the human brain, the activity of OGDHc is a rate-limiting step in the Krebs cycle [1,2,4,5,76,96] and the activity of hPDHc was found to be five-fold higher than that of hOGDHc [97]. This ratio was ~3 (mitochondrion) or ~7 (intact cell) in fibroblasts and ~1.5 (mitochondrion) or ~15 (intact cell) in leukocytes [98].
Individual recombinant components of pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes (PDHc, OGDHc) of human and Escherichia coli (E. coli) origin were expressed and purified from E. coli with optimized protocols. The four multienzyme complexes were each reconstituted under optimal conditions at different stoichiometric ratios. Binding stoichiometries for the highest catalytic efficiency were determined from the rate of NADH generation by the complexes at physiological pH. Since some of these complexes were shown to possess ‘moonlighting’ activities under pathological conditions often accompanied by acidosis, activities were also determined at pH 6.3. As reactive oxygen species (ROS) generation by the E3 component of hOGDHc is a pathologically relevant feature, superoxide generation by the complexes with optimal stoichiometry was measured by the acetylated cytochrome c reduction method in both the forward and the reverse catalytic directions. Various known affectors of physiological activity and ROS production, including Ca²⁺, ADP, lipoylation status or pH, were investigated. The human complexes were also reconstituted with the most prevalent human pathological mutant of the E3 component, G194C and characterized; isolated human E3 with the G194C substitution was previously reported to have an enhanced ROS generating capacity. It is demonstrated that: i. PDHc, similarly to OGDHc, is able to generate ROS and this feature is displayed by both the E. coli and human complexes, ii. Reconstituted hPDHc generates ROS at a significantly higher rate as compared to hOGDHc in both the forward and the reverse reactions when ROS generation is calculated for unit mass of their common E3 component, iii. The E1 component or E1-E2 subcomplex generates significant amount of ROS only in hOGDHc; iv. Incorporation of the G194C variant of hE3, the result of a disease-causing mutation, into reconstituted hOGDHc and hPDHc indeed leads to a decreased activity of both complexes and higher ROS generation by only hOGDHc and only in its reverse reaction.
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