What is Mitochondrial Biogenesis? Benefits & Effects

Key Learning Objectives

• Learn about mitochondrial biogenesis, the creation of new mitochondria 
• Discover some of the molecules that regulate mitochondrial biogenesis
• Understand why making new mitochondria is important for healthy aging
• Find out which dietary ingredients help us make new mitochondria

Introduction to Mitochondrial Biogenesis

Mitochondrial biogenesis is the cellular process that produces new mitochondria. It’s one of the ways cells adapt to the ever-changing energy requirements dictated by environmental and physiological conditions. Under circumstances of decreased fuel supply, such as caloric restriction, or of increased energy demand, such as exercise, cells have to adjust their metabolic processes to maintain the availability of cellular energy (as ATP) to meet the energetic needs of tissues.

When metabolic stimuli are fleeting and mild, cells can quickly adapt by adjusting what they use for fuel based on what’s available. For example, if blood sugar (i.e., glucose) is in short supply, they may switch from preferentially using glucose to using fatty acids as the primary fuel, while simultaneously activating pathways that maintain blood glucose at constant levels.

But, upon prolonged or intense metabolic challenges, cells need to step it up a notch, upregulating their capacity to make more ATP. In these situations, cells may have to enhance their energy production machinery, including their mitochondrial networks. This involves a whole set of processes, from changes in genetic expression and protein production, to the assembly of new cellular structures of energy production. Because cell energy production is dependent on mitochondria, this is where mitochondrial biogenesis, the creation of new mitochondria, steps in.

Mitochondrial biogenesis is important not only to respond to metabolic challenges, but also to maintain mitochondrial integrity. Mitochondrial biogenesis, along with mitophagy and fission/fusion (discussed in Mitochondria Functions For Healthy Aging), are essential for mitochondrial homeostasis, for the segregation and selective elimination of damaged mitochondria and, importantly, for the regeneration of the mitochondrial network.

There’s a growing appreciation that mitochondrial biogenesis plays a substantial role in healthspan—the length of time that the person is healthy. Mitochondrial biogenesis helps the cell to renew the mitochondrial network and, consequently, to improve mitochondrial function, slowing down the cascade of damage caused by mitochondrial dysfunction (one of the twelve hallmarks of aging).

Similar to many other cellular processes, mitochondrial biogenesis, and the interacting pathways that influence it, suffers with aging. This is the bad news. The good news is that there are things we can do to better support maintaining a fitter mitochondrial network.

Mitochondrial Biogenesis Explained

Mitochondrial biogenesis is the cellular process that produces new mitochondria. But mitochondria cannot be produced from scratch (de novo); new mitochondria are produced by adding new content—proteins, membranes—to pre-existing mitochondria.

Mitochondria form a dynamic network that can change shape and size. These changes, known as mitochondrial dynamics, are driven by two complementary processes: mitochondrial fission and fusion. Through mitochondrial fission, smaller mitochondria are created to which new mitochondrial content can be added in mitochondrial biogenesis. This upgraded mitochondrion can then fuse back with the existing mitochondrial network, to create a larger and more elongated mitochondrion, that will be more efficient in the generation of cell energy. The result of this mitochondrial biogenesis is, effectively, an increase in mitochondrial mass.[1,2]

Mitochondrial biogenesis is complementary to another process of mitochondrial quality control that removes damaged or dysfunctional mitochondria segregated by mitochondrial fission called autophagy (or mitophagy, in the specific case of mitochondrial autophagy)—a process by which a cell degrades and recycles damaged proteins and organelles. Mitophagy and mitochondrial biogenesis sustain mitochondrial turnover to maintain optimal mitochondrial function.[3]

Mitochondrial biogenesis can be upregulated as part of a concerted adaptive cellular response to metabolic challenges. This response increases ATP output and manages ATP expenditure in times of need. The increase in mitochondrial mass resulting from mitochondrial biogenesis is accompanied by an increase in the mitochondrial machinery for fatty acid oxidation, the citric acid cycle, and oxidative phosphorylation, enhancing the cell’s capacity to produce ATP from food.

Certain herbs and dietary supplements have been reported to support increased mitochondrial mass or number. These include the herbs Kaempferia parviflora (common name black ginger or black turmeric),[4] Rosmarinus officinalis (rosemary; source of ursolic acid),[5] and the plant polyphenols apigenin,[6] rutin,[7,8] and resveratrol.[9,10] Mitochondrial supportive compounds such as coenzyme Q10 (CoQ10; ubiquinone),[11,12] lipoic acid,[13] and pyrroloquinoline quinone (PQQ) [14,15] support bigger more efficient mitochondrial networks.

Mitochondrial biogenesis is somewhat similar to muscles growing bigger and stronger with exercise. It results in fitter mitochondria able to make more ATP.

What is mtDNA?

Mitochondria have their own DNA, the mitochondrial DNA (mtDNA). mtDNA is normally inherited exclusively from the mother. It is made up of multiple copies of small circular DNA that encodes only 13 essential proteins of the electron transport chain (ETC) complexes, as well as 2 rRNAs and 22 tRNAs needed for the production of those proteins.[16] The vast majority of mitochondrial proteins are encoded by nuclear DNA (nDNA; the DNA we inherit from both parents) and then imported into mitochondria. Therefore, the crosstalk between the two types of DNA assumes a very important role in mitochondrial biogenesis.

Mitochondrial biogenesis is a complex process that requires the replication (multiplication) of mtDNA, transcription and translation of mtDNA and nuclear DNA genes (the processes that produce proteins from DNA), mitochondrial membrane recruitment and extension, protein import, protein allocation to different mitochondrial compartments, and assembly of the electron transport chain complexes in the mitochondrial membrane. And all this is carried out in coordination with the dynamics of the existing mitochondrial network.[17]

It takes both nuclear DNA (inherited from both parents) and mitochondrial DNA (normally inherited exclusively from the mother) for mitochondrial biogenesis.

Nutritional support for mtDNA includes grape extracts, with both the grape proanthocyanidins [18] and resveratrol [9,19,20] components supporting mtDNA. The mitochondrial ingredients creatine,[21] CoQ10,[11] lipoic acid,[13] PQQ[14,15,22] have been reported to support mtDNA.

How Cells Coordinate Mitochondrial Biogenesis

Cells detect information and decide how to respond. The response occurs, in a general sense, by turning on and off genes. But at any point in time, a cell might have to weigh many different pieces of information before deciding how to change gene expression. They decide what to do with the help of transcription factors.

Transcription factors are proteins that help regulate the transcription (i.e., copying) of genetic material. Many genes are regulated by multiple transcription factors, which allows cells to combine different sources of information to decide whether to express a gene. The activity of multiple transcription factors is coordinated by transcription coactivators.

At the core of the orchestration of mitochondrial biogenesis is a family of transcription coactivators: peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), PGC-1β, and PGC-1-related coactivator (PRC).[23] They are coactivators of peroxisome proliferator-activated receptors (PPARα, γ, and δ), which have key roles in modulating fat metabolism, including mitochondrial fatty acid oxidation.[24]

PGC-1α, PGC-1β and PRC activate similar pathways and have similar effects in the regulation of mitochondrial biogenesis. But whereas PGC-1α and PGC-1β are found in higher levels in tissues that contain abundant mitochondria (e.g., heart, skeletal muscle, brown fat), PRC is expressed in higher levels in proliferating cells (i.e., the process that results in an increase of the number of cells). Furthermore, the expression and activity of PGC-1α can be induced by a variety of stimuli in a tissue-specific manner: calorie restriction in the liver, exercise in skeletal muscle, and cold in brown adipose tissue (BAT). PGC-1β is not induced by these cues.[25]

Therefore, PGC-1α is primarily associated with mitochondrial biogenesis in contexts of energy demand, PGC-1β participates in basal mitochondrial biogenesis, and PRC is associated with mitochondrial biogenesis in contexts of cell growth and cell division.[25]

Accordingly, PGC-1α is involved in several hormonal and nutrient signaling pathways that modulate energy metabolism and other cellular processes in response to environmental and physiological cues, promoting an adaptation to increased energy demand, including mitochondrial biogenesis. Because many of those pathways that regulate the expression of the mitochondrial machinery converge in PGC-1α, it is regarded as the “master regulator of mitochondrial biogenesis.” PGC-1α can drive virtually all aspects of mitochondrial biogenesis, including transcription of electron transport chain and mitochondrial metabolic pathways genes.[17]

Supporting two transcription coactivators—PGC-1α and PGC-1β— upregulates mitochondrial biogenesis.

Only a few phytochemicals have been reported to support PGC-1β. Ursolic acid, which is found in plants including rosemary and apple peel, is one of them. In mice, ursolic acid has substantially upregulated PGC-1β in the liver and hypothalamus.[26,27] Rutin, when combined with exercise, supports fat tissue PGC-1β in mice fed a high-fat diet.[28]

There are far more options available for supporting PGC-1α. Options include foods like dark chocolate (cocoa extracts),[29–31] an herb called Kaempferia parviflora (common name black ginger or black turmeric),[4,32,33] plant phytochemicals such as the proanthocyanidins [18,34,35] and resveratrol [9,10,36] from grapes, apple polyphenols,[37–39] citrus bioflavonoids (i.e., hesperidin, nobiletin),[40–42] apigenin,[6] rutin,[7,8,28] and ursolic acid.[5] The mitochondrial ingredients CoQ10,[11,43] lipoic acid,[13,44,45] and PQQ,[14,15,22] as well as two supplements often used for sports performance, creatine [21] and β-Hydroxy-β-Methylbutyric acid (HMB),[46] also support PGC-1α.

How PGC-1α Coordinates Mitochondrial Biogenesis

PGC-1α is often described as being the master regulator of mitochondrial biogenesis. This is because it coordinates the activity of nuclear and mitochondrial transcription factors, and the crosstalk between them. This allows the cellular genome and the mitochondrial genome to act together to build the proteins needed for mitochondrial biogenesis.

PGC-1α induces mitochondrial biogenesis by stimulating the genetic expression of two transcription factors called nuclear respiratory factor 1 (NRF1) and nuclear respiratory factor 2 (NRF2). NRF1 and NRF2 ensure the coordination between nuclear and mitochondrial genomes. This coordination is essential because some of the proteins needed for mitochondrial biogenesis are made outside the mitochondria from cellular DNA, while others are made inside mitochondria from mtDNA.

NRF1 and NRF2 modulate the expression of nuclear DNA-encoded molecules, including several mitochondrial proteins and mitochondrial transcription factor A (TFAM).[47] TFAM is required for the transcription of mtDNA-encoded proteins and for mtDNA replication.[48] Therefore, by increasing the nuclear expression of TFAM, PGC-1α can also indirectly increase the expression of proteins encoded by mtDNA.

PGC-1α also promotes mitochondrial biogenesis by activating estrogen-related receptor alpha (ERRα), a nuclear receptor preferentially expressed in tissues with high capacity for β-oxidation of fatty acids, such as skeletal muscle.[49]

ERRα, NRF1 and NRF2 are required for PGC-1α to increase the expression of several genes encoding proteins involved in fatty acid oxidation, oxidative phosphorylation, mitochondrial dynamics and mitochondrial biogenesis.

The activity of PGC-1α depends on its expression levels, subcellular localization, and post-transcriptional modifications. PGC-1α is produced in an inactive form and accumulates in the cytoplasm; when it is activated either by phosphorylation or deacetylation, it accumulates in the nucleus (and mitochondria) and promotes mitochondrial biogenesis.

Ingredients that support upregulation of the transcription factors of mitochondrial biogenesis (e.g., NFR1, NFR2, EERα, Tfam) include: (1) cocoa extract,[31,50,51] Kaempferia parviflora,[32] apigenin,[6] grape proanthocyanidins[18,52,53] and resveratrol,[9,36,54] citrus bioflavonoids (i.e., nobiletin, hesperidin),[55–57] rutin,[7,8] ursolic acid,[5] CoQ10,[11] lipoic acid,[13,45] PQQ,[14,15,22] and HMB.[46]

When a cell has decided it needs to make more ATP, PGC-1α coordinates the activity of nuclear and mitochondrial transcription factors, so the needed genes are turned on and off at the right times.

What Upregulates PGC-1α Activity?

PGC-1α is positively regulated by several signaling molecules and pathways used to sense the energy supply of the cell and adapt to physiological stressors. Two energy sensors—AMP-activated protein kinase (AMPK) and sirtuins—play a key role in the upregulation of mitochondrial biogenesis through the activation of PGC-1α. The cAMP/PKA/CREB signaling pathway can also activate PGC-1α.

AMPK is a signaling molecule that is activated in response to an increased AMP/ATP ratio. So, when ATP synthesis is diminished, or ATP is being consumed at a high rate (such as during intense exercise), AMPK becomes more active. In this role, AMPK acts as an ATP sensor that signals the cell energy status of the cell.[58]

AMPK can be upregulated by cocoa extract,[29,31,59] Kaempferia parviflora,[32,33] Gynostemma pentaphyllum,[60,61] apigenin,[6,62,63] grape proanthocyanidins [34,35,53] and resveratrol,[10,36,64] cinnamon,[65–67] citrus bioflavonoids (i.e., nobiletin, hesperidin),[40,56,68] strawberry seed polyphenols,[69,70] compounds within rosemary including ursolic acid,[5,71,72] rutin,[7,28,73] CoQ10,[11,43,74] lipoic acid,[44,45,75] PQQ,[15] creatine,[21,76,77] and HMB.[46,78]

Sirtuins are a class of proteins involved in cellular stress response. Sirtuin activation requires the redox molecule NAD⁺ as cofactor. (see NAD⁺ CONSUMPTION USES: AN OVERVIEW) Sirtuin activity is NAD⁺-dependent and is upregulated by increases in NAD⁺ levels and/or a higher NAD⁺/NADH ratio. Therefore, sirtuins act as NAD⁺ sensors that signal the energy-related redox status of the cell.[79]

Sirtuins can be supported by many of the same ingredients as AMPK. These include cocoa extract,[29,31,59] Kaempferia parviflora,[32,80] apigenin,[81] grape proanthocyanidins [18,34,52] and resveratrol,[19,54,82] cinnamon,[83,84] citrus bioflavonoids (i.e., nobiletin, hesperidin),[40,55] strawberry seed polyphenols,[69,85] compounds within rosemary including ursolic acid,[26,27,86] rutin,[7,8,87] CoQ10,[11,43,74] lipoic acid,[45,88,89] PQQ,[15] and HMB.[46,78] Other ingredients that support sirtuins are the Ayurvedic herb Withania somnifera (Ashwagandha) [90] and apple polyphenols.[91]

By sensing ATP and NAD⁺, AMPK and sirtuins paint a clear picture of the energy status and requirements of the cell at any given moment. They also act together to help cells restore ATP levels in the near term, and increase the capacity to make more ATP for the future. 

Both AMPK and sirtuins, more specifically the sirtuin SIRT1, target signaling pathways that influence mitochondrial biogenesis to increase the energy production capacity of the cell. And they do so via PGC-1α: AMPK activates PGC-1α through phosphorylation;[92] SIRT1 activates PGC-1α through deacetylation.[93] Furthermore, AMPK and SIRT1 co-activate each other to further strengthen the signal.[19,94]

Another sirtuin, SIRT3, also has an important role in mitochondrial biogenesis. SIRT3 is activated by a higher NAD⁺/NADH ratio, with its expression stimulated by PGC-1α.[95] SIRT3 is found within mitochondria, where it regulates many important aspect of mitochondrial function. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid oxidation and the electron transport chain, increasing mitochondrial energy metabolism and ensuring that the new mitochondrial content is fully functional.[96]

Cyclic AMP (cAMP) is another regulator of mitochondrial biogenesis. cAMP signaling can be upregulated by fasting, exercise, and exposure to cold.[97] Increased cAMP levels activate protein kinase A (PKA), which in turn activates (phosphorylates) the transcription factor cAMP response element-binding protein (CREB). CREB in turn upregulates the expression of PGC-1α.[47] PKA also directly activates SIRT1.[98]

Ingredients that upregulate cAMP-PKA-CREB signaling include theobromine (found in cocoa extract),[99] ursolic acid,[100] and lipoic acid.[101]

Reactive oxygen species (ROS) are generated by the mitochondrial electron transport chain and act as signaling molecules. Increases in ROS production signal dysfunctions in the electron transport chain and in ATP production, triggering a set of adaptive stress responses, including mitochondrial biogenesis. They can do so via PGC-1α.[102]

Therefore, via activation by AMPK, SIRT1, cAMP/PKA/CREB, or ROS, PGC-1α levels can be upregulated to trigger an adaptive response to physiological stimuli, such as caloric restriction, exercise, cold, or oxidative stress.[17]

Behaviors including exercise, fasting, and cold exposure help promote healthy aging. PGC-1α sits at the crossroads of several cellular signaling pathways, ensuring that fitter mitochondrial networks are produced in response to these behaviors.

How Thyroid Hormone Promotes Mitochondrial Biogenesis

The thyroid hormones (TH) thyroxine (T₄) and triiodothyronine (T₃) are key regulators of metabolism. Among other effects, they increase the basal metabolic rate, regulate carbohydrate, fat, and protein metabolism, and promote thermogenesis (i.e, heat production) in brown adipose tissue, thereby having a significant influence on cell energy generation. Accordingly, TH (in the more active form T₃) is known to have a significant impact on several aspects of mitochondrial function.[103]

Stimulating mitochondrial biogenesis is one of the main actions of T₃.[104] Binding of T₃ to nuclear thyroid hormone receptors induces the expression of PGC-1α and increases the production of a number of nDNA-encoded mitochondrial proteins.[103]

TH-induced PGC-1α expression can upregulate ERRα and increase NRF1, TFAM, and mtDNA levels in an ERRα-dependent manner. Consequently, TH activates activate major mitochondrial metabolic pathways regulated by the PGC-1α/ERRα interaction: not only mitochondrial biogenesis, but also oxidative phosphorylation, fatty acid oxidation, citric acid cycle, mitochondrial dynamics, and mitophagy.[105]

Supporting healthier thyroid function is an important part of enhancing both overall mitochondrial performance and biogenesis. Ingredients that support thyroid function include Withania somnifera (Ashwagandha),[106–108] inositol (e.g., myo-inositol, D-chiro-inositol),[109–111] and rutin.[112,113]

Healthy Aging Benefits of Mitochondrial Biogenesis

An age-related decline in mitochondrial biogenesis has been shown to be associated with a loss of mitochondrial mass and a decline in mitochondrial function, particularly in high energy-demanding tissues such as skeletal muscle, heart, and brain. Increased mitochondrial biogenesis, on the other hand, can alleviate mitochondrial dysfunction and boost cellular function.[114]

The pathways that regulate mitochondrial biogenesis are known to affect longevity and there are a number of interventions that have been shown to promote health and longevity by (among other effects) improving mitochondrial biogenesis.[115]

There is evidence that an age-associated decline of PGC-1α levels may be among the main causes of loss of mitochondrial biogenesis capacity.[116] Therefore, supporting the expression, activation and activity of PGC-1α is a key target in the support of mitochondrial biogenesis.

For healthier aging we need our cells to selectively get rid of defective mitochondria and replace them, through mitochondrial biogenesis, with higher performing ones.

While science informs us that mitochondrial biogenesis performance declines with aging, there are things we can do to push back against this decline. Exercise (especially weight training and high-intensity interval training ([HIIT]), fasting-related behaviors, and challenging the body with hot and cold therapies support fitter mitochondria. As Dr. Jack Kruse mentioned in a Collective Insights podcast, spending more time in nature can have a powerful effect on how mitochondria perform. And, lastly diet plays a large role: eating more of certain foods, and taking specific dietary supplements, can support mitochondrial biogenesis and therefore healthy aging.

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