Mitochondrial biogenesis

Last updated December 14, 2024

Mitochondrial biogenesis is the process by which cells increase mitochondrial numbers.^[1]^[2] It was first described by John Holloszy in the 1960s, when it was discovered that physical endurance training induced higher mitochondrial content levels, leading to greater glucose uptake by muscles.^[3] Mitochondrial biogenesis is activated by numerous different signals during times of cellular stress or in response to environmental stimuli, such as aerobic exercise.^[1]^[2]^[4]

Background

The ability for a mitochondrion to self-replicate is rooted in its evolutionary history. It is commonly thought that mitochondria descend from cells that formed endosymbiotic relationships with α-protobacteria; they have their own genome for replication.^[5] However, recent evidence suggests that mitochondria may have evolved without symbiosis.^[6] The mitochondrion is a key regulator of the metabolic activity of the cell, and is also an important organelle in both production and degradation of free radicals.^[7] It is postulated that higher mitochondrial copy number (or higher mitochondrial mass) is protective for the cell.

Mitochondria are produced from the transcription and translation of genes both in the nuclear genome and in the mitochondrial genome. The majority of mitochondrial protein comes from the nuclear genome, while the mitochondrial genome encodes parts of the electron transport chain along with mitochondrial rRNA and tRNA. Mitochondrial biogenesis increases metabolic enzymes for glycolysis, oxidative phosphorylation and ultimately a greater mitochondrial metabolic capacity. However, depending on the energy substrates available and the redox state of the cell, the cell may increase or decrease the number and size of mitochondria.^[8] Critically, mitochondrial numbers and morphology vary according to cell type and context-specific demand, whereby the balance between mitochondrial fusion/fission regulates mitochondrial distribution, morphology, and function.^[9]^[8]

Protein import

Since the majority of mitochondrial protein comes from the nuclear genome, the proteins need to be properly targeted and transported into the mitochondria to perform their functions.^[8]^[10]^[11] First, mRNA is translated in the cell's cytosol.^[10]^[11] The resulting unfolded precursor proteins will then be able to reach their respective mitochondrial compartments.^[11]^[10] Precursor proteins will be transported to one of four areas of the mitochondria, which include the outer membrane, inner membrane, intermembrane space, and matrix.^[10]^[11] All proteins will enter the mitochondria by a translocase on the outer mitochondrial membrane (TOM).^[11]^[10]^[5] Some proteins will have an N-terminal targeting signal, and these proteins will be detected and transported into the matrix, where they will then be cleaved and folded.^[12]^[11]^[10] Other proteins may have targeting information in their sequences and will not include an N-terminal signal.^[11]^[10] During the past two decades, researchers have discovered over thirty proteins that participate in mitochondrial protein import.^[11] As researchers learn more about these proteins and how they reach the respective mitochondrial compartments that utilize them, it becomes evident that there is a multitude of processes that work together in the cell to allow for mitochondrial biogenesis.^[11]^[8]

Fusion and fission

Mitochondria are highly versatile and are able to change their shape through fission and fusion events.^[9]^[8] Definitively, fission is the event of a single entity breaking apart, whereas fusion is the event of two or more entities joining to form a whole.^[8] The processes of fission and fusion oppose each other and allow the mitochondrial network to constantly remodel itself.^[9]^[8] If a stimulus induces a change in the balance of fission and fusion in a cell, it could significantly alter the mitochondrial network.^[9]^[13] For example, an increase in mitochondrial fission would create many fragmented mitochondria, which has been shown to be useful for eliminating damaged mitochondria and for creating smaller mitochondria for efficient transporting to energy-demanding areas.^[13]^[14] Therefore, achieving a balance between these mechanisms allows a cell to have the proper organization of its mitochondrial network during biogenesis and may have an important role in muscle adaptation to physiological stress.^[13]

In mammals, mitochondrial fusion and fission are both controlled by GTPases of the dynamin family.^[8]^[13] The process of mitochondrial fission is directed by Drp1, a member of the cytosolic dynamin family.^[8]^[9] This protein forms a spiral around mitochondria and constricts to break apart both the outer and inner membranes of the organelle.^[14] On the other hand, the process of fusion is directed by different membrane-anchored dynamin proteins at different levels of the mitochondria.^[13] Fusion at the level of the outer mitochondrial membrane is mediated by Mfn1 and Mfn2 (Mitofusins 1 and 2),^[15] and fusion at the level of the inner mitochondrial membrane is mediated by Opa1.^[8]^[12]^[13] Multiple research studies have observed correlated increases between mitochondrial respiratory capacity with Mfn1, Mnf2, and Drp1 gene expression after endurance exercises.^[14]^[15] Therefore, it is supported that reorganization of the mitochondrial network in muscle cells plays an important role in response to exercise.^[4]^[13]^[15]

Regulation

PGC-1α, a member of the peroxisome proliferator-activated receptor gamma (PGC) family of transcriptional coactivators, is the master regulator of mitochondrial biogenesis.^[1]^[2]^[16] It is known to co-activate nuclear respiratory factor 2 (NRF2/GABPA), and together with NRF-2 coactivates nuclear respiratory factor 1 (NRF1).^[15]^[16] The NRFs, in turn, activate the mitochondrial transcription factor A (tfam), which is directly responsible for transcribing nuclear-encoded mitochondrial proteins.^[15]^[16] This includes both structural mitochondrial proteins as well as those involved in mtDNA transcription, translation, and repair.^[16] PGC-1β, a protein that is structurally similar to PGC-1α, is also involved in regulating mitochondrial biogenesis, but differs in that it does not get increased in response to exercise.^[5]^[17]^[16] While there have been significant increases in mitochondria found in tissues where PGC-1α is overexpressed, as the cofactor interacts with these key transcription factors, knockout mice with disrupted PGC-1α are still viable and show normal mitochondrial abundance.^[17]^[5]^[16] Thus, PGC-1α is not required for normal development of mitochondria in mice, but when put under physiological stress, these mice exhibit diminished tolerance compared to mice with normal levels of PGC-1α.^[5]^[16]^[17] Similarly, in knockout mice with disrupted PGC-1β, the mice showed mostly normal levels of mitochondrial function with decreased ability to adapt to physiological stress.^[18]^[5] However, a double knockout experiment of PGC-1α/β created mice that died mostly within 24 hours by defects in mitochondrial maturation of cardiac tissue.^[19] These findings suggest that while both PGC-1α and PGC- 1β do not each solely establish a cell's ability to perform mitochondrial biogenesis, together they are able to complement each other for optimal mitochondrial maturation and function during periods of physiological stress.^[19]^[5]^[17]

AMP-activated kinase (AMPK) also regulates mitochondrial biogenesis by phosphorylating and activating PGC-1α upon sensing an energy deficiency in muscle.^[5]^[16] In mice with reduced ATP/AMP ratios that would occur during exercise, the energy depletion has been shown to correlate with AMPK activation.^[5]^[18]^[16] AMPK activation then continued to activate PGC- 1α and NRFs in these mice, and mitochondrial biogenesis was stimulated.^[5]^[18]^[16]

Aging

The capacity for mitochondrial biogenesis has been shown to decrease with age, and such decreased mitochondrial function has been associated with diabetes and cardiovascular disease.^[20]^[21]^[22] Aging and disease can induce changes in the expression levels of proteins involved in the fission and fusion mechanisms of mitochondria, thus creating dysfunctional mitochondria.^[23]^[24] One hypothesis for the detrimental results of aging is associated with the loss of telomeres, the end segments of chromosomes that protect genetic information from degradation.^[21]^[24] Telomere loss has also been associated with decreased mitochondrial function.^[24]^[21] Deficiency of telomerase reverse transcriptase (TERT), an enzyme that plays a role in preserving telomeres, has been correlated with activated p53, a protein that suppresses PGC-1α.^[24]^[23]^[21] Therefore, the loss of telomeres and TERT that comes with aging has been associated with impaired mitochondrial biogenesis.^[21]^[23]^[24] AMPK expression has also been shown to diminish with age, which may also contribute to suppressing mitochondrial biogenesis.^[5]^[24]

Clinical Applications of Targeting Mitochondrial Biogenesis

Mitochondrial biogenesis can be targeted to prevent cancer proliferation. Specifically, two biogenesis regulators—PGC1α and c-Myc—can be targeted to prevent cancer proliferation. PGC1α is a key component in mitochondrial biogenesis—as a transcriptional coactivator, it targets multiple transcription factors and the estrogen-related receptor alpha (ERRα).^[25] Compounds that target the pathway between PGC1α and ERRα, such as the ERRα inverse agonist, XCT-790, have been found to significantly decrease mitochondrial biogenesis, thus greatly reducing cancer cells’ proliferation and increasing their sensitivity to chemotherapeutic agents.^[26] c-Myc, a transcription factor, can be inhibited during its dimerization with Max protein by molecules such as IIA6B17^[27] and omomyc.^[28] Inhibition of the c-Myc-Max complex can block the cell cycle and induce apoptosis in cancer cells.

Related Research Articles

A mitochondrion (pl. mitochondria) is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. Meaning a thread-like granule, the term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase popularized by Philip Siekevitz in a 1957 Scientific American article of the same name.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the cytoplasm of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs—ACACA and ACACB.

The ERRs are orphan nuclear receptors, meaning the identity of their endogenous ligand has yet to be unambiguously determined. They are named because of sequence homology with estrogen receptors, but do not appear to bind estrogens or other tested steroid hormones.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.

Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternate transcriptional splice variants, which encode the same protein, have been characterized. Additional variants encoding different protein isoforms have been described but they have not been fully characterized. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor -like 1" which has an official symbol of NFE2L1.

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

<span class="mw-page-title-main">Fibroblast growth factor 21</span> Protein-coding gene in mammals

Fibroblast growth factor 21 (FGF-21) is a protein that in mammals is encoded by the FGF21 gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily which includes FGF23 and FGF15/19. FGF21 is the primary endogenous agonist of the FGF21 receptor, which is composed of the co-receptors FGF receptor 1 and β-Klotho.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">FNDC5</span>

Fibronectin type III domain-containing protein 5, the precursor of irisin, is a type I transmembrane glycoprotein that is encoded by the FNDC5 gene. Irisin is a cleaved version of FNDC5, named after the Greek messenger goddess Iris.

Mitochondrial fission is the process by which mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by mitochondrial fusion, where two mitochondria fuse together to form a larger one. Fusion can result in elongated mitochondrial networks. In healthy cells, mitochondrial fission and fusion are balanced, and disruptions to these processes are linked to various diseases. Mitochondrial fission is coordinated with the mitochondrial DNA replication process. Some of the proteins involved in mitochondrial fission have been identified, and mutations in some of these proteins are associated with mitochondrial diseases. Mitochondrial fission plays a role in the cellular stress response and in apoptosis.

Mitochondria are dynamic organelles with the ability to fuse and divide (fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the health of the cell, and defects in dynamics lead to genetic disorders. Through fusion, mitochondria can overcome the dangerous consequences of genetic malfunction. The process of mitochondrial fusion involves a variety of proteins that assist the cell throughout the series of events that form this process.

The mitochondrial unfolded protein response (UPR^mt) is a cellular stress response related to the mitochondria. The UPR^mt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. The UPR^mt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. In the UPR^mt, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly. UPR^mt causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.

Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation. In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria.

Immunometabolism is a branch of biology that studies the interplay between metabolism and immunology in all organisms. In particular, immunometabolism is the study of the molecular and biochemical underpinninngs for i) the metabolic regulation of immune function, and ii) the regulation of metabolism by molecules and cells of the immune system. Further categorization includes i) systemic immunometabolism and ii) cellular immunometabolism. Immunometabolism includes metabolic inflammation:a chronic, systemic, low grade inflammation, orchestrated by metabolic deregulation caused by obesity or aging.

David A. Hood is a Canadian professor, exercise physiologist, and Director of the Muscle Health Research Centre at York University. A holder of an NSERC Tier I Canada Research Chair in Cell Physiology, Hood is credited with making significant research advances in understanding of the biology of exercise, mitochondria and muscle health.

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