section 14.3
Mitochondrial Energy States
TABLE 14-4
Energy States o f Mitochondria*
State 1
State 2
State 3
State 4
State 5
ADP level
Substrate level
Approaching 0
Respiration rate
acceptor (ADP)
acceptor (ADP)
*Reproduced, with permission, from B. Chance and G. R. Williams: Respiratory enzymes in oxidative phosphorylation: the steady state.
J . B i o l .
C h e m .
carbonyl groups of the peptide bonds. Unlike valinomycin
and nigericin, gramicidin A forms a static pore in the
14.3 Mitochondrial Energy States
Normal mitochondria can exist in one of five energy states
(Table 14-4). In the presence of nonlimiting amounts of
respiratory chain components, the rate of oxygen con-
sumption is affected by changes in the NADH/NAD+
ratio, the phosphorylation ratio (or phosphate potential,
[ATP]/[ADP][P;]), and p 0 2. In a resting (unstimulated)
mitochondrion, in the presence of nonlimiting concen-
trations of substrate (reductant), oxygen, and phosphate,
respiratory activity is controlled by the availability of
ADP (state 4, Table 14-4). In this state, the rate of en-
dogenous energy dissipation is low and is regulated by
ADP. On addition of ADP, the respiratory rate increases
dramatically (state 3) until the ADP supply is depleted.
Repeated ADP-induced respiratory cycles between states
4 and 3 cause depletion of substrate (state 2), phos-
phate, or oxygen. If oxygen is unavailable, respiration
ceases (state 5). Dinitrophenol abolishes respiratory con-
trol because it uncouples the transport of reducing equiv-
alents in the respiratory chain from the phosphorylation
of ADP.
In the oxidation of carbohydrates, energy is conserved
at all three stages: glycolysis, TCA cycle, and oxidative
phosphorylation. Each of these stages is regulated at spe-
cific sites, and all three are coordinated in such a man-
ner that ATP is synthesized only to the extent that it is
needed in the cell. For example, when the [ATP]/[ADP]
ratio is high, glycolysis, TCA cycle, and oxidative phos-
phorylation are inhibited. The key regulatory enzyme,
-phosphofructokinase, is activated by ADP and inhibited
by ATP (see also Chapters 13, 15, and 22.)
Energy-Linked Functions of Mitochondria
Other Than ATP Synthesis
The energy derived from the respiratory chain, although
primarily coupled to the formation of ATP, is also utilized
for purposes such as heat production, ion transport, and
the transhydrogenase reaction.
Brown adipose tissue is responsible for nonshivering
thermogenesis, which is important in the arousal of hiber-
nating animals and for maintaining body temperature in
hairless neonates of mammals, including humans. Diet-
induced thermogenesis also occurs in brown adipose tis-
sue (Chapter 12). Brown adipose tissue, in contrast to
white adipose tissue, consists of small cells that are rich
in mitochondria and lipid dispersed in the cytoplasm as
distinct droplets. Mitochondria of brown adipose tissue
are naturally uncoupled, so that oxidation of substrates
generates heat rather than a proton-motive force. The in-
ner mitochondrial membrane contains, instead of the nor-
mal proton-translocating channel in Fo, an H+ uniport
that causes the dissipation of energy as heat without the
concomitant synthesis of ATP. When the requirement for
thermogenesis ceases, the H+ uniport is blocked by a
protein called
(M.W. 32,000). Thermogenin
becomes functional after binding to purine nucleotides,
of which GDP is the most effective and ADP and ATP
are less effective. This protein recouples phosphorylation
with the energy released in the respiratory chain. It is lo-
cated at the entrance to the H+ channel on the C side
of the inner membrane. Stimulation of thermogenesis in
brown adipose tissue is initiated by stimulation of the sym-
pathetic nervous system, which releases norepinephrine
at nerve endings. Norepinephrine combines with the /3-
adrenergic receptors of the brown adipose tissue cells and
initiates cAMP-dependent activation of triacylglycerol li-
pase (Chapter 22), leading to the elevated intracellular
concentrations of fatty acids that are oxidized in the mito-
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