59
is by oxidation of NADHA/FADH 2 via glycolysis. In addition to glycolysis, other
mechanisms are also involved in generating NADH2/FADH2; these are the TCA
cycle, oxidative phosphorylation, and β-oxidation of fatty acids. These processes
are controlled by transcription factors present in mitochondria and there are about
800–1000 copies of mtDNA present in the single mitochondrion that is inherited
and packaged in nucleoids [8]. However, nucleoids are widely spread in the matrix
of mitochondria but mostly reside in the vicinity of cristae. Cristae is an organelle
that carries the OXPHOS system. Between inner and outer membrane there is a
small space present which is called intermembrane space. The outer and intramembranous space of mitochondria has more penetration power than the inner membrane. The permeability of the inner membrane is low because the inner membrane
has enzymes that perform the ETC process to generate ATP. The mitochondrial
matrix is surrounded by a mitochondrial membrane where the TCA cycle produces
electrons that are taken up by ETC to produce ATP. The OXPHOS process is derived
through the production of electrochemical gradient across the inner membrane [9].
The electron transport chain contains five subunits of enzyme complexes. These
are complex I (NADH ubiquinone reductase), complex II (succinate dehydrogenase), complex III (Ubiquinol-cytochrome c reductase), complex IV (cytochrome c
oxidase), and complex V (F 0 F 1 ATP synthase). They are located in the inner mitochondrial membrane [10]. Electrons are donated by the TCA cycle which then travel
to the electron transport chain. These electrons travel from enzyme complex I to
V. Transport of protons is also coupled with the transfer of electrons along the ETC
that generate electrochemical gradient which produces ATP [11]. Mitochondria
continuously produce reactive species by metabolizing oxygen. The electron flow
through the electron transport chain is an imperfect process. Mitochondria consume
incompletely reduced oxygen and produce reactive species such as (•O
−2
) which is
also called “Primary” ROS [12]. The secondary ROS is also generated due to the
excessive generation of primary ROS [13]. It has been proved that the deoxyribose,
backbone of DNA, i.e., a nitrogenous base, purine and pyrimidine, damages due to
the interlinking of hydroxyl radical with DNA [2]. The increased production of
reactive species causes damage in mitochondrial proteins/enzymes, DNA, and other
cell structures as a result of an abnormality in mitochondrial functioning and failure
to produce ATP in mitochondria [12]. The electron transport chain also generates
other reactive species of nitrogen. Nitration induced by reactive nitrogen species is
affected by cellular proteins and glutathione. Similarly, free radicals which are produced freely can also inhibit the oxidative damage both by enzymatic and nonenzymatic mechanism. The mechanisms involved can scavenge free radicals by
antioxidants or lead to generation of free radicals.
The oxidative stress which is produced by increased release of free radicals can
be overcome by several defense mechanisms. The following are involved in enzymatic defense mechanism such as SOD, CAT, GR, and GPx. Similarly, the nonenzymatic defense system possesses antioxidant compounds such as Vitamin C and
E, glutathione, etc. The ionic imbalance produces damage in the cells which causes
other abnormalities to appear in the cell including impairment of enzymatic functions which further degrade the mitochondrial function [5]. In diabetes, the number
3 Mitochondrial Dysfunction in Metabolic Disorders
is by oxidation of NADHA/FADH 2 via glycolysis. In addition to glycolysis, other
mechanisms are also involved in generating NADH2/FADH2; these are the TCA
cycle, oxidative phosphorylation, and β-oxidation of fatty acids. These processes
are controlled by transcription factors present in mitochondria and there are about
800–1000 copies of mtDNA present in the single mitochondrion that is inherited
and packaged in nucleoids [8]. However, nucleoids are widely spread in the matrix
of mitochondria but mostly reside in the vicinity of cristae. Cristae is an organelle
that carries the OXPHOS system. Between inner and outer membrane there is a
small space present which is called intermembrane space. The outer and intramembranous space of mitochondria has more penetration power than the inner membrane. The permeability of the inner membrane is low because the inner membrane
has enzymes that perform the ETC process to generate ATP. The mitochondrial
matrix is surrounded by a mitochondrial membrane where the TCA cycle produces
electrons that are taken up by ETC to produce ATP. The OXPHOS process is derived
through the production of electrochemical gradient across the inner membrane [9].
The electron transport chain contains five subunits of enzyme complexes. These
are complex I (NADH ubiquinone reductase), complex II (succinate dehydrogenase), complex III (Ubiquinol-cytochrome c reductase), complex IV (cytochrome c
oxidase), and complex V (F 0 F 1 ATP synthase). They are located in the inner mitochondrial membrane [10]. Electrons are donated by the TCA cycle which then travel
to the electron transport chain. These electrons travel from enzyme complex I to
V. Transport of protons is also coupled with the transfer of electrons along the ETC
that generate electrochemical gradient which produces ATP [11]. Mitochondria
continuously produce reactive species by metabolizing oxygen. The electron flow
through the electron transport chain is an imperfect process. Mitochondria consume
incompletely reduced oxygen and produce reactive species such as (•O
−2
) which is
also called “Primary” ROS [12]. The secondary ROS is also generated due to the
excessive generation of primary ROS [13]. It has been proved that the deoxyribose,
backbone of DNA, i.e., a nitrogenous base, purine and pyrimidine, damages due to
the interlinking of hydroxyl radical with DNA [2]. The increased production of
reactive species causes damage in mitochondrial proteins/enzymes, DNA, and other
cell structures as a result of an abnormality in mitochondrial functioning and failure
to produce ATP in mitochondria [12]. The electron transport chain also generates
other reactive species of nitrogen. Nitration induced by reactive nitrogen species is
affected by cellular proteins and glutathione. Similarly, free radicals which are produced freely can also inhibit the oxidative damage both by enzymatic and nonenzymatic mechanism. The mechanisms involved can scavenge free radicals by
antioxidants or lead to generation of free radicals.
The oxidative stress which is produced by increased release of free radicals can
be overcome by several defense mechanisms. The following are involved in enzymatic defense mechanism such as SOD, CAT, GR, and GPx. Similarly, the nonenzymatic defense system possesses antioxidant compounds such as Vitamin C and
E, glutathione, etc. The ionic imbalance produces damage in the cells which causes
other abnormalities to appear in the cell including impairment of enzymatic functions which further degrade the mitochondrial function [5]. In diabetes, the number
3 Mitochondrial Dysfunction in Metabolic Disorders