in a process of endosymbiosis, eucaryotic cells have mitochondria which was originally derived from an aerobic alpha-proteobacteria very early in evolution
all eukaryotes contain either bacteria-like mitochondria with bacterial DNA or, in exceptional cases, remnants of it
procaryotes do not have mitochondria
mitochondria cannot survive outside the cell presumably as some of the alpha-proteobacteria genes have been transferred to the host cell DNA
each mitochondrion measures between 1 to 10 µm in length and has two membrane layers with the outer layer equating to a vacuole which engulfed the alpha-proteobacterium
the outer membrane has many protein-based pores that are big enough to allow the passage of ions and molecules as large as a small protein
the inner membrane has much more restricted permeability, much like the plasma membrane of a cell and is loaded with proteins involved in electron transport and ATP synthesis
each cell has a “mitochondrial pool”:
eukaryotic cells contain varying amounts of mitochondria, depending on the cells’ energy needs
most somatic cells contain 300-400 mitochondria, female ova contain 100,000 perhaps “fresh unused mitochondria” (in female embryos some are stored away in the developing ovaries in their pristine state)
sperm only contains a few dozen as it needs to be small and fast and mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM) — the major nucleoid protein required to protect, maintain and transcribe mtDNA1)
sexual reproduction involves passing on not only genes but also all the rest of the fertilized egg, including live stored mitochondria from the maternal ovum
Overview of roles of mitochondria
aerobic energy production via ATP production and utilising oxygen and substrates in “cellular respiration”/“Kreb's cycle” and are the primary producers of CO2 and free radicals - reactive oxygen species (ROS)
the brain is a major user of mitochondria consuming 25% of body energy, a resting cortical neuron consumes 4.7 billion ATP molecules per second and a resting human brain uses nearly 6 kilograms of ATP per day
the brain (and other organs) is not able to function if mitochondrial function becomes impaired
heat production
this is a natural byproduct of cellular respiration
it is actively used for thermogenesis such as by brown adipose tissue
general cellular control
they determine whether a cell should live or die
they determine whether a stem cell should differentiate and into what type of cell
mitochondria control the clock that wakes stem cells up from dormancy
to stay dormant, stem cells rely on glycolysis (breaking down sugar outside the mitochondria), which keeps their metabolic activity very low.
when mitochondria switch over to oxidative phosphorylation (using oxygen inside the mitochondria to generate massive amounts of ATP), they send a hard chemical signal telling the stem cell it is time to wake up and divide
if a stem cell needs to put the brakes on division — such as avoiding overgrowth or surviving stress — it triggers mitophagy (the targeted destruction of its own mitochondria), clearing out active mitochondria forces the cell back into a safe, non-dividing state
mitochondria use physical shape changes and chemical messengers to guide a stem cell toward its new identity
specific levels of ROS can act as a text message to the cell nucleus, activating specialized genes that trigger differentiation into specific cell lines
mitochondrial size has a role in determining type of cell to differentiate into
mitochondria produce intermediate ingredients (like Acetyl-CoA and alpha-ketoglutarate) which physically alter the packing of DNA in the nucleus, unlocking the specific genes
when a stem cell undergoes asymmetric division — meaning it splits into one new stem cell (to keep the pool alive) and one differentiating cell (to go build tissue) — mitochondria decide which cell is which - during division, the stem cell pushes the youngest, cleanest mitochondria into the daughter cell destined to remain a stem cell.
they determine when cells should divide
modulate cellular gene expression via retrograde signaling
insert their own mtDNA into somatic cell DNA (NUMTs)
mitochondria actively regulate, sustain, and feedback into the body's 24-hour cycle
mitochondria are deeply involved in the synthesis and metabolism of major circadian hormones (eg. cortisol)
NB. whilst 95% of the body production of melatonin is via local mitochondria, this is not circadian but produced as needed by the mitochondria - circadian melatonin is produced by the pineal gland cytoplasm via AANAT enzyme and constitutes the remaining 5% of total body melatonin synthesis
when you wake up and encounter daylight, mitochondria in your cells fuse into long, interconnected networks. This structural change makes them highly efficient at generating the surging energy (ATP) needed for your daytime cognitive and physical activities, in addition, mitochondria ramp up the production of enzymes required to burn carbohydrates and lipids, preparing the body for breakfast and daytime energy consumption
as you stay awake, the continuous burden of aerobic metabolism stresses the mitochondria and they begin to fragment into smaller pieces (fission).
this structural breakdown and the resulting cellular stress act as a primary signal to the brain, building up “sleep pressure” and telling your body it is time to rest
artificially forcing mitochondrial fusion or fission in animal studies directly alters how long and how deeply they sleep
at night, the mitochondria switch priorities from energy production to cellular housekeeping - they scale down ATP production and ramp up mitophagy (self-cleaning) and antioxidant defenses to repair the molecular damage accumulated during the day and the glymphatic system of the brain helps to remove waste products from neurons
melatonin is not just a brain signal, it is also a potent antioxidant which helps safeguard mitochondria from oxidative stress during your sleep cycle
mitochondria produce a crucial coenzyme called NAD+ (nicotinamide adenine dinucleotide).
the levels of NAD+ rise and fall rhythmically based on mitochondrial activity and acts as a chemical messenger to the cell's nucleus
NAD+ activates specific proteins (like SIRT1 and SIRT3) that directly control the master “clock genes” (such as BMAL1 and CLOCK).
if mitochondria suffer from dysfunction and stop producing these rhythmic chemical signals, the entire cellular body clock loses its rhythm, leading to metabolic imbalances
participate in control of the whole body including during embryogenesis
they synthesize and produce the steroid hormones such as the sex hormones, cortisol, etc
act as social organelles that send stress and signaling molecules to distant tissues
have a role in immunity and inflammation
via the production of free radicals which can be utilized to kill pathogens
can trigger inflammatory responses via leaking mtDNA and ROS
produce a range of other critical substances:
heme
citrate which is then exported into the cell to build fatty acids, lipids and nucleotides
urea cycle intermediates which help process and detoxify ammonia derived from amino acid breakdown
although the traditional view is that eucaryotes embedded an aerobic bacterium as mitochondria to provide much greater energy efficiencies, given the amount of control mitochondria have, it could be viewed that mitochondria took control of the eucaryote cell and gradually evolved the cell to create functional organs to provide oxygen and fuel for the mitochondria
Mitochondrial DNA (mtDNA)
mitochondria have their own DNA (in early evolution this was derived from a bacterium and in humans is 37 genes but each mitochondrion may have hundreds of copies of these)
mitochondrial genomes are very small and show a great deal of variation as a result of divergent evolution
mitochondrial genes that have been conserved across evolution include rRNA genes, tRNA genes, and a small number of genes that encode proteins involved in electron transport and ATP synthesis
some of the codons that mitochondria use to specify amino acids differ from the standard eukaryotic codons
the vast majority of mitochondrial proteins are synthesized from the cell's nuclear genes and transported into the mitochondria
mtDNA is inherited only from the maternal mtDNA (with some very rare exceptions)
mtDNA is a circular DNA molecule composed of 16,568 base pairs, divided into heavy and light strands2)
it primarily encodes 13 protein subunits of the electron transport chain, two rRNAs (16S and 12S), and 22 tRNAs
unlike diploid nuclear DNA, mtDNA is polyploid, with tens to thousands of copies per cell, and healthy cells exhibit relatively low levels of mtDNA mutations
due to the lack of protective histones and limited error correction mechanisms, the mtDNA mutation rate is 100 times higher than that of nuclear DNA
Mitochondrial reproduction within a cell
mitochondria contain their own circular DNA, special ribosomes, and transfer RNAs thus they are semi-autonomous and split independently of the cell's main nucleus
mitochondria exist in a constant, fluid cycle of splitting apart (fission) and merging together (fusion)
their reproduction is synchronized with the activity and division of the cell
fusion allows damaged mitochondria to merge with healthy ones, sharing resources and undamaged DNA to repair themselves
fission
a cell will trigger replication whenever its energy demands increase
for instance, when a person undergoes consistent physical training, their muscle cells will rapidly prompt mitochondria to multiply to keep up with the need for ATP
fission can also isolate permanently damaged parts of a mitochondrion so the cell can recycle them, ensuring the overall population stays highly efficient (“mitophagy”)
main steps of fission:
biogenesis
it must first grow and duplicate its internal components
replicates its own mtDNA using specialised polymerase enzymes sent from the cell nucleus
synthesises a small portion of its own proteins internally and imports the rest from the surrounding cytoplasm to expand both its inner and outer membranes
fission
divides into two
process begins where the cell's endoplasmic reticulum (ER) wraps around the mitochondrion, initiating a preliminary squeeze
specialized cytosolic proteins — primarily a molecular motor called Dynamin-Related Protein 1 (Drp1) — are recruited to a constriction site where they form a tight ring structure around the outside of the mitochondrion
powered by chemical energy (GTP hydrolysis), the Drp1 ring constricts violently, pinching and sealing both the inner and outer membranes to separate the parent organelle into two healthy daughter mitochondria
Mitochondrial processes
this mtDNA creates the mitochondria and its processes
ATP energy production
a prime role is in producing energy for the cell in the form of ATP via oxidative phosphorylation and the Krebs cycle but this requires acetyl-CoA (from pyruvate which is from glucose), oxygen and co-factors such as NADH, FAD, ADP; and the waste products are CO2, water and potentially damaging free radicals which need to be neutralized by anti-oxidants they make or are provided to them
mitochondria act as both regulators and mediators of Reactive Oxygen Species (ROS), balancing cellular survival and apoptosis and are the primary producers of ROS
mitochondrial repair and stress processes:
pairs of malfunctioning mitochondria fuse together and come apart again; in the process, the best components of each pair are left in one mitochondrion and the other is targeted for destruction, but if too many dysfunctional ones are present the cell may undergo apoptosis (via release of cytochrome c from leaky mitochondria)
there are many other roles of mitochondria:
mitochondria are involved in regulating cellular metabolism, health and longevity, cell death, tumour microenvironment, autophagy, and cell fate3)
Mitochondrial stress responses:
retrograde signaling to the cell's nuclear DNA to alter the cell's gene expression:
when mitochondria experience stress, they send signals back to the cell nucleus (and outward to other cells) to alter gene expression, regulate the Mitochondrial Unfolded Protein Response (UPRmt), and influence systemic resilience
inter-tissue communication:
mitochondria appear to act as social organelles that send stress and signaling molecules to distant tissues - when mitochondrial function is disrupted in one part of the body, it can trigger adaptive or damaging responses throughout the entire organism 4)
trigger systemic inflammatory response:
inflammaging and immune activation:
damaged mitochondria leak mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) into the cell and bloodstream. These act as danger signals that activate inflammatory pathways (like the cGAS-STING and NLRP3 inflammasomes), driving chronic, low-grade systemic inflammation known as inflammaging
cellular aging:
stem cell exhaustion:
mitochondrial decay in stem cells reduces their capacity to regenerate tissues, accelerating functional aging across organs
role in control of cell cycles, body clock, etc
NUMTs
the transfer of mitochondrial DNA into the nuclear genomes of somatic cells
potential interaction with the earth's magnetosphere
potential hybrid quantum effects
an anomalous 71.0-THz oscillation mode (=4222nm infrared light) only in living cells and tissues was found and it seems to arise from a quantum superposition state of functional mitochondrion forms by the coupling of light and lipid CH2 bonds in functional cristae, and induces a splitting of the intrinsic CH2 vibration mode of 87 THz to two levels at 71 THz and 103 THz5)