2. Introduction:
What are Mitochondria?
Mitochondria are double-membraned organelles found in the cells of most
eukaryotic organisms. Often referred to as the "powerhouses of the cell,"
mitochondria play a crucial role in cellular respiration, the process by which
cells generate energy in the form of adenosine triphosphate (ATP).
3. Origin of Mitochondria by Endosymbiotic
theory:
The origin of mitochondria is a fascinating topic in the field of evolutionary
biology, and it is explained by the endosymbiotic theory. The endosymbiotic
theory proposes that mitochondria originated from a symbiotic relationship
between a primitive eukaryotic cell and an ancestral prokaryotic cell.
Around 1.5 billion years ago, complex cells called eukaryotes emerged,
containing a nucleus and other membrane-bound organelles. The
endosymbiotic theory suggests that mitochondria were once free-living
prokaryotes that established a symbiotic relationship with an ancestral
eukaryotic cell.
The theory proposes that a primitive eukaryotic cell engulfed a free-living
aerobic prokaryote, possibly an ancestor of modern-day alpha-proteobacteria.
This initial event of endosymbiosis involved the eukaryotic cell taking in the
prokaryotic cell but not digesting it. Instead, the prokaryote survived and started
to thrive within the host cell.
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Over time, this symbiotic relationship became mutually beneficial. The
prokaryote provided the host cell with a rich supply of energy through aerobic
respiration, producing adenosine triphosphate (ATP) via the electron transport
chain. The host cell, in turn, provided a protected environment and nutrients for
the prokaryote.
Gradually, the prokaryotic endosymbiont evolved into an organelle, losing many
genes that were no longer necessary due to the host cell's support. The host
cell and the endosymbiont became interdependent, with the endosymbiont
providing energy to the host and the host providing protection and resources to
the endosymbiont.
This symbiotic relationship resulted in the formation of mitochondria as we
know them today. Mitochondria have a double membrane structure, similar to
prokaryotic cells, with an inner membrane that contains the proteins involved in
energy production. They also possess their own DNA, which is distinct from the
nuclear DNA of the host cell. This DNA encodes some of the proteins essential
for mitochondrial function.
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Evidence supporting the endosymbiotic theory includes the similarities between
mitochondria and free-living bacteria. Mitochondria, like bacteria, have their
own circular DNA, reproduce independently of the host cell, and have
ribosomes similar to those found in bacteria. Additionally, mitochondria are
similar in size to prokaryotes and have a similar membrane structure.
Furthermore, the endosymbiotic theory is supported by the fact that
mitochondria are found in almost all eukaryotic cells, including plants, animals,
fungi, and protists. The theory also explains the origin of chloroplasts in
photosynthetic eukaryotes, which are thought to have originated from a similar
endosymbiotic event involving a photosynthetic prokaryote and a eukaryotic
host cell.
In conclusion, the endosymbiotic theory provides a compelling explanation for
the origin of mitochondria. It suggests that these organelles evolved from a
symbiotic relationship between an ancestral eukaryotic cell and an aerobic
prokaryote, leading to the mutualistic integration of the prokaryote into the host
cell as mitochondria. This theory has had a profound impact on our
understanding of cellular evolution and the complex origins of eukaryotic life.
6. Typical characteristics of mitochondria:
Here are the typical characteristics of mitochondria:
1. Size: Mitochondria vary in size, but on average, they are about 0.5 to 1
micrometer in diameter and 2 to 10 micrometers in length. However, their size can
change dynamically based on the cell's energy requirements.
2. Shape: Mitochondria often have an elongated and tubular shape, although their
morphology can be highly diverse across different cell types. They can appear as
long rods, curved structures, or even interconnected networks of branched tubules.
The shape of mitochondria can change dynamically through processes such as
fusion and fission.
3. Abundance: The number of mitochondria in a cell can vary depending on the
cell type, energy demands, and physiological state. Typically, cells with high energy
requirements, such as muscle cells, contain a larger number of mitochondria. For
instance, liver cells can have hundreds to thousands of mitochondria, while red
blood cells do not have mitochondria at all.
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4. Double-membrane structure: Mitochondria have two distinct membranes—an
outer membrane and an inner membrane—that enclose the organelle. The outer
membrane is smooth and surrounds the entire mitochondrion, while the inner
membrane has numerous folds called cristae. These cristae significantly increase
the surface area available for various metabolic processes.
5. Cristae and matrix: The inner membrane of mitochondria contains cristae,
which are invaginations or folds that project into the matrix, the central
compartment of the mitochondrion. The cristae play a crucial role in the generation
of ATP (adenosine triphosphate), the primary energy currency of cells. The matrix
contains enzymes, DNA, ribosomes, and other components necessary for
mitochondrial function.
6. Powerhouse of the cell: Mitochondria are often referred to as the
"powerhouses of the cell" due to their central role in cellular energy production.
They carry out aerobic respiration, a process that converts nutrients into ATP
through a series of metabolic reactions, including the citric acid cycle and oxidative
phosphorylation.
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7. Endosymbiotic origin: Mitochondria are thought to have originated from
ancient symbiotic bacteria that were engulfed by ancestral eukaryotic cells billions
of years ago. This endosymbiotic event is supported by several pieces of evidence,
including the presence of their own DNA, reproduction through fission, and
similarities in structure and function to free-living bacteria.
10. The outer membrane of mitochondria:
The outer membrane of mitochondria is one of the two membranes that
surround this double-membraned organelle found in eukaryotic cells. It plays a
crucial role in protecting and maintaining the structure and function of the
mitochondria.
Structure: The outer membrane is a phospholipid bilayer composed of proteins
and lipids. It is relatively porous and contains large channel proteins called
porins, which allow the passage of ions, metabolites, and other small
molecules. The outer membrane is smooth and lacks the invaginations and
folds seen in the inner membrane.
11. Functions of outer membrane:
Functions:
1. Physical Barrier: The outer membrane acts as a physical barrier, separating
the contents of the mitochondria from the cytoplasm of the cell. It provides
protection to the inner components of the mitochondria by preventing the entry of
harmful molecules or substances.
2. Transport of Small Molecules: The porin proteins present in the outer
membrane allow the passage of small molecules (less than 10 kDa) across the
membrane. This includes ions like calcium (Ca2+), metabolites, and other
molecules necessary for mitochondrial function, such as ADP (adenosine
diphosphate) and ATP (adenosine triphosphate).
3. Interaction with the Cell: The outer membrane of mitochondria interacts with
other cellular components and organelles. It forms contact sites with the
endoplasmic reticulum (ER), which facilitate the exchange of lipids, calcium ions,
and other molecules between the two organelles. These interactions play a role in
various cellular processes, including lipid metabolism and calcium signaling.
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4. Protein Import: The outer membrane contains protein complexes responsible
for the import of proteins into the mitochondria. These protein import channels,
such as the TOM (Translocase of the Outer Membrane) complex, recognize and
transport proteins synthesized in the cytoplasm into the mitochondria, allowing
them to perform their specific functions within the organelle.
5. Metabolic Signaling: The outer membrane also participates in metabolic
signaling pathways. It houses enzymes involved in lipid metabolism, such as
phospholipases and acyltransferases, which contribute to the synthesis and
remodeling of mitochondrial membranes.
13. The inner membrane of mitochondria:
The highly folded inner membrane of mitochondria, known as cristae, is a
distinctive feature of these organelles. The cristae are formed by invaginations
of the inner mitochondrial membrane that extend into the matrix, creating a
series of narrow, finger-like projections or folds. These folds significantly
increase the surface area of the inner membrane, providing ample space for
various biochemical reactions and facilitating the efficient production of ATP
(adenosine triphosphate), the cell's primary energy currency.
The structure of cristae varies between different cell types and their functional
needs. In general, the cristae display a complex and interconnected network of
folds, which can be arranged in various patterns, including tubular, disc-like, or
lamellar shapes. The folding patterns contribute to the structural integrity and
stability of the cristae, ensuring that they maintain their shape and function even
under dynamic cellular conditions.
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The cristae contain numerous protein complexes and enzymes that are crucial
for the electron transport chain and oxidative phosphorylation, the two main
processes responsible for ATP synthesis in mitochondria. These protein
complexes, including the electron transport chain components and ATP
synthase, are embedded within the inner membrane and are organized in a
way that allows for the efficient transfer of electrons and protons during ATP
production.
The presence of cristae is essential for the proper functioning of mitochondria.
The increased surface area provided by the folds enables a higher density of
protein complexes involved in ATP synthesis. This arrangement allows
mitochondria to generate ATP more efficiently and meet the energy demands of
the cell. Additionally, the cristae help to segregate various metabolic reactions
within the mitochondria, separating the processes involved in ATP production
from other cellular functions taking place in the mitochondrial matrix.
15. Matrix:
The matrix of mitochondria refers to the innermost compartment of these
organelles, enclosed by the inner mitochondrial membrane. It is a gel-like
substance that fills the space between the inner membrane and the highly
folded structures known as cristae.
The inner membrane of mitochondria is impermeable to most molecules,
creating a distinct environment within the organelle. The matrix contains a
variety of enzymes, DNA, RNA, ribosomes, and other proteins necessary for
the mitochondria to carry out its functions.
The matrix plays a critical role in several biochemical processes that are
essential for cellular energy production. One of its primary functions is to house
the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid
cycle. This cycle is a central pathway for generating energy-rich molecules,
such as adenosine triphosphate (ATP), through the breakdown of nutrients like
glucose.
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In addition to energy production, the matrix is also involved in other metabolic
pathways, such as fatty acid oxidation, amino acid metabolism, and the
synthesis of certain molecules. It contains enzymes responsible for these
reactions, enabling mitochondria to participate in diverse cellular processes
beyond energy generation.
Furthermore, the matrix is the site of mitochondrial DNA (mtDNA) replication
and transcription. Mitochondria have their own genetic material, separate from
the DNA in the cell's nucleus. The matrix contains the necessary machinery to
replicate and transcribe this mitochondrial DNA, allowing the organelles to
produce some of their own proteins independently.
Overall, the matrix of mitochondria serves as a crucial compartment where
various metabolic reactions occur, enabling the organelles to produce energy,
synthesize molecules, and carry out essential cellular functions.
17. Composition of the matrix of mitochondria
including enzymes, mitochondrial DNA,
ribosomes, and small molecules.
The matrix of mitochondria is a complex and dynamic environment that plays a
crucial role in the functioning of these organelles. It contains various
components, including enzymes, mitochondrial DNA (mtDNA), ribosomes, and
small molecules, all of which contribute to the mitochondrial metabolic
processes.
Enzymes: The matrix of mitochondria houses numerous enzymes that are
involved in a wide range of biochemical reactions. These enzymes are
responsible for key metabolic pathways such as the citric acid cycle (also
known as the Krebs cycle or TCA cycle), fatty acid oxidation, amino acid
metabolism, and the electron transport chain. Some notable enzymes found in
the matrix include pyruvate dehydrogenase, isocitrate dehydrogenase,
succinate dehydrogenase, and ATP synthase.
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Mitochondrial DNA (mtDNA): Mitochondria possess their own unique DNA,
distinct from the nuclear DNA found in the cell's nucleus. The mitochondrial
DNA is circular in shape and carries genes essential for the synthesis of
mitochondrial proteins. It encodes a small portion of the mitochondrial enzymes
and plays a vital role in mitochondrial function and replication. The mtDNA is
located in the matrix region of mitochondria, where it is closely associated with
the inner mitochondrial membrane.
Ribosomes: Mitochondria contain their own ribosomes, known as mitochondrial
ribosomes or mitoribosomes. These ribosomes are responsible for the
synthesis of mitochondrial proteins using the information encoded in the
mitochondrial DNA. Mitochondrial ribosomes are structurally and functionally
distinct from the ribosomes found in the cytoplasm, reflecting the evolutionary
origins of mitochondria as independent, symbiotic bacteria.
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Small Molecules: The matrix of mitochondria also contains various small
molecules that participate in metabolic processes. These include cofactors such
as NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine
dinucleotide), which serve as electron carriers in redox reactions. Coenzyme Q
(CoQ), a lipid-soluble molecule, is also present in the matrix and plays a crucial
role in the electron transport chain. Additionally, the matrix contains metabolites
involved in the citric acid cycle, such as citrate, isocitrate, alpha-ketoglutarate,
succinate, and malate.
20. Functions of Mitochondria:
1. ATP PRODUCTION:
Electron Transport Chain (ETC):
1. The process begins in the inner mitochondrial membrane, where electrons derived
from the breakdown of carbohydrates, fats, and proteins (through processes such as
glycolysis and beta-oxidation) enter the electron transport chain.
2. Electrons are passed through a series of protein complexes embedded in the inner
mitochondrial membrane: NADH dehydrogenase (Complex I), succinate
dehydrogenase (Complex II), cytochrome bc1 complex (Complex III), and
cytochrome c oxidase (Complex IV).
3. As electrons are transferred between these complexes, protons (H+) are pumped
from the mitochondrial matrix into the intermembrane space, creating an
electrochemical gradient.
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Chemiosmosis:
1. The proton gradient generated by the electron transport chain drives ATP synthesis
through a process known as chemiosmosis.
2. ATP synthase, located in the inner mitochondrial membrane, acts as a molecular
machine that utilizes the proton gradient to generate ATP.
3. As protons flow back into the mitochondrial matrix through ATP synthase, the energy
released is harnessed to convert ADP (adenosine diphosphate) and inorganic
phosphate (Pi) into ATP. This process is called phosphorylation.
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ATP Yield:
1. The exact number of ATP molecules produced per molecule of NADH or FADH2
varies depending on the stoichiometry of the electron transport chain and
chemiosmosis.
2. NADH generated in glycolysis and the citric acid cycle can yield approximately 2.5 to
3 ATP molecules, while FADH2 generated in the citric acid cycle produces about 1.5
to 2 ATP molecules.
3. The overall ATP yield from the complete oxidation of glucose is approximately 30 to
32 ATP molecules, considering all the metabolic pathways involved.
23. 2. Metabolic reaction:
Mitochondria play a crucial role in various metabolic pathways within cells,
including the citric acid cycle, also known as the Krebs cycle or tricarboxylic
acid (TCA) cycle. The mitochondria are considered the powerhouse of the cell
because they are the primary site for energy production in the form of
adenosine triphosphate (ATP). Let's explore how mitochondria participate in
these metabolic pathways, focusing on the citric acid cycle.
Citric Acid Cycle (Krebs cycle): The citric acid cycle is a central metabolic
pathway that takes place within the mitochondria. It involves a series of
enzymatic reactions that oxidize acetyl-CoA, derived from the breakdown of
carbohydrates, fats, and proteins, to produce ATP, reducing equivalents (NADH
and FADH2), and carbon dioxide (CO2).
24. 3. Homeostasis and Ca regulation:
1. Calcium Uptake: Mitochondria possess specialized transport proteins called
the mitochondrial calcium uniporter (MCU) that actively transport calcium ions
from the cytoplasm into the mitochondrial matrix. This transport is driven by the
electrochemical gradient across the inner mitochondrial membrane. The MCU
allows mitochondria to take up calcium ions when the cytoplasmic
concentration of calcium is elevated.
2. Calcium Release: When the cytoplasmic calcium concentration decreases,
mitochondria can release calcium back into the cytoplasm. This release is
mediated by the mitochondrial permeability transition pore (mPTP) and other
calcium efflux channels present on the inner mitochondrial membrane. The
release of calcium from mitochondria can occur in response to various cellular
signals or stimuli.
3. Calcium Buffering: Mitochondria act as intracellular calcium buffers, helping to
maintain the overall calcium concentration within the cell. The mitochondrial
matrix contains calcium-binding proteins, such as calbindin, which can bind to
and sequester calcium ions. By sequestering calcium, mitochondria prevent
excessive cytoplasmic calcium accumulation, which could lead to cellular
dysfunction and damage.
25. 4. Apoptosis:
1. Mitochondrial Outer Membrane Permeabilization (MOMP): One of the early
events in apoptosis is the release of pro-apoptotic proteins from the mitochondrial
intermembrane space. These proteins, such as cytochrome c, Smac/DIABLO, and
Omi/HtrA2, are normally confined within the mitochondria. MOMP refers to the loss
of integrity of the mitochondrial outer membrane, allowing the release of these
proteins into the cytosol.
2. Cytochrome c Release and Apoptosome Formation: Once released into the
cytosol, cytochrome c binds to an adaptor protein called Apaf-1 (Apoptotic
protease-activating factor 1), forming a complex known as the apoptosome. This
complex recruits and activates procaspase-9, initiating a cascade of caspase
activations, leading to cell death.
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3. Mitochondrial Membrane Potential (ΔΨm) Collapse: During apoptosis, there
is a disruption of the mitochondrial electron transport chain, resulting in a decrease
in mitochondrial membrane potential. This collapse of ΔΨm is considered a point of
no return in the apoptotic process. It leads to the opening of the mitochondrial
permeability transition pore (MPTP) and the release of additional apoptotic factors.
4. Apoptotic Factors Release: In addition to cytochrome c, mitochondria also
release other pro-apoptotic factors, including apoptosis-inducing factor (AIF) and
endonuclease G. These factors translocate to the nucleus and participate in the
degradation of DNA, contributing to the execution of apoptosis.
5. Energy Depletion: The disruption of mitochondrial function during apoptosis
results in a decrease in ATP production. This energy depletion contributes to the
breakdown of cellular processes and eventual cell death.
27. 5. Thermogenesis:
Brown adipose tissue (BAT) mitochondria play a crucial role in generating heat
through a process called non-shivering thermogenesis. This unique
characteristic of brown adipose tissue is responsible for its ability to regulate
body temperature and contribute to energy expenditure.
Mitochondria are the powerhouses of cells, responsible for generating
adenosine triphosphate (ATP) through oxidative phosphorylation. However, in
brown adipose tissue, mitochondria possess a special protein called uncoupling
protein 1 (UCP1) that enables the dissipation of energy as heat rather than ATP
production.
The primary function of UCP1 is to uncouple the electron transport chain from
ATP synthesis. Under specific conditions, such as exposure to cold
temperatures or certain hormones, sympathetic nervous system stimulation
triggers the activation of BAT. Signals from the sympathetic nervous system
cause the release of norepinephrine, which binds to specific receptors on brown
adipocytes.
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Upon stimulation, UCP1 in the inner mitochondrial membrane of brown
adipocytes is activated. It forms a channel that allows the flow of protons (H+)
across the mitochondrial membrane, bypassing the ATP synthase complex. As
a result, the energy derived from the oxidation of fatty acids or glucose is
converted into heat instead of ATP production.
This uncoupling process creates a proton gradient across the inner
mitochondrial membrane, which dissipates the electrochemical potential across
the mitochondrial membrane. The energy released as heat warms the
surrounding tissue, contributing to the maintenance of body temperature.
Additionally, brown adipose tissue mitochondria possess a higher density of
thermogenic enzymes, such as cytochrome c oxidase and pyruvate
dehydrogenase, compared to mitochondria found in other tissues. This
increased enzyme density further enhances the capacity of BAT mitochondria to
generate heat.
29. 6. Role of Mitochondria in Health and
Disease:
Mitochondrial dysfunction is closely associated with diseases such as
mitochondrial myopathies and Leigh syndrome. Both of these conditions are
characterized by abnormalities in mitochondrial function, leading to a wide
range of symptoms and complications.
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Mitochondrial myopathies:
Mitochondrial myopathies are a group of genetic disorders that primarily
affect the skeletal muscles. These conditions result from mutations in genes
responsible for mitochondrial function and energy production. The mitochondria
are the cellular powerhouses responsible for generating adenosine triphosphate
(ATP), the main source of energy for cellular processes. In mitochondrial
myopathies, the dysfunction of mitochondria impairs ATP production, leading to
muscle weakness, fatigue, and exercise intolerance. Common symptoms may
include muscle pain, difficulty swallowing, droopy eyelids (ptosis), and
progressive weakness. Some of the well-known mitochondrial myopathies
include Kearns-Sayre syndrome, MELAS syndrome (mitochondrial
encephalomyopathy, lactic acidosis, and stroke-like episodes), and MERRF
syndrome (myoclonic epilepsy with ragged red fibers).
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Leigh syndrome:
Leigh syndrome, also known as Leigh disease, is a severe neurological
disorder that typically affects infants and young children. It is characterized by
progressive degeneration of the central nervous system, including the
brainstem and basal ganglia. Leigh syndrome is often caused by mutations in
nuclear or mitochondrial genes involved in mitochondrial function. The
dysfunction of mitochondria in Leigh syndrome leads to energy deficiency and
the accumulation of toxic byproducts within cells, causing neurological
impairments. Symptoms of Leigh syndrome may include developmental delay,
loss of motor skills, muscle weakness, seizures, respiratory problems, and
feeding difficulties.
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The association between mitochondrial dysfunction and these diseases arises
from the crucial role of mitochondria in cellular energy production and various
metabolic processes. Mutations in genes responsible for mitochondrial function
impair the electron transport chain and disrupt oxidative phosphorylation, the
processes essential for ATP synthesis. As a result, affected tissues, such as
skeletal muscles or the central nervous system, experience energy deficits,
leading to the specific symptoms observed in mitochondrial myopathies and
Leigh syndrome.
