Mitochondrial regeneration and the relationship with NAD+

Mitochondria are tiny structures present inside the cells that are essential for our survival. They are known as the "Power House of the Cell" because they generate energy to drive our body. Essential organs like the brain, heart, kidney, and muscles have the highest amount of mitochondria to meet their high metabolic demands. In order to generate energy from glucose, mitochondria needs a co-enzyme that can accept and donate high-energy hydrogen ions and electrons. Nicotinamide (NAD+) is the best co-enzyme that has the tendency to work with and without oxygen. A major portion of the NAD+ is located in the mitochondria to facilitate this process of ATP production.

Mitochondria experiences deterioration in their structural and functional during cellular senescence (aging). Mitochondrial damage results in impaired energy production and harmful reactive oxygen species(ROS) accumulation. Mitochondrial dysfunction is also the underlying mechanism in many neurological diseases, including Parkinson's disease and Leigh syndrome. Therefore, mitochondrial regeneration is required to maintain an appropriate high-quality mitochondrial level.

The body has a mechanism to remove these damaged mitochondria known as "Mitophagy" and replace them with the new one by "Mitochondrial Biogenesis." NAD+ is also essential for mitochondrial regeneration as it delays mitochondrial aging, reduces oxidative stress, repairs DNA, and stimulates stem cells.

NAD+ level in the cells provides information about the nutrition status of the body. When the NAD+ level is high, a signal is sent to start the replication of cells, as nutrients are abundant. A decreased NAD+ level tells the body to stop regeneration due to low nutrients. Gregory McElroy and his colleagues conducted a study and demonstrated that improvement in NAD level decreased brain inflammation and increased lifespan of patients with mitochondrial dysfunction. (McElroy et al. 2020)

Role of NAD+ level in mitochondrial regeneration:

There are various mechanisms by which the NAD+ level is linked to Mitochondrial damage and regeneration. Some of them are discussed below:

1-    Improvement in Stem Cells Function:

Stem cells are located in the bone marrow, gastrointestinal tract, and skin cells. They are essential to maintain the integrity of all cells and require NAD for their proper functioning. They continuously proliferate to make up for the damaged and aged cells. If the number of stem cells is reduced, all cells, including mitochondria, undergo progressive degeneration and atrophy.

However, like everything else, stem cells also age, and their number is reduced. Nicotinamide supplementation improves metabolic functioning, delays aging, and increases the mitochondria's life span.

Researchers have confirmed that NAD+ supplementation slows down the aging process of the stem cells and improves mitochondrial regeneration. (Hongbo et al. 2016)

2-    Increased activity of Sirtuins :

The role of Sirtuins in mitochondrial degradation and regeneration is well understood. Sirtuin-1 has been shown to activate the degradation of the damaged mitochondria by mitophagy. Sirtuin-1 and Sirtuin-3 then stimulate mitochondrial biogenesis by activating an enzyme called PGC-1a. The whole procedure increases the mitochondrial turnover and results in an increase in mitochondrial quality.

NAD+ function as a cofactor and a potent stimulator of Sirtuins.  Any change in the NAD+ level of the body affects the Sirtuins activity. When the activity of the Sirtuins is compromised, non-functioning mitochondria accumulate in the body and result in aging.

A study done in Switzerland has shown that NAD+ administration increased Mitochondrial biogenesis due to increased activity of SIRT-I deacetylase. These researchers also recommended that NAD+ supplementation can be used to treat mitochondrial dysfunction. (Cantó et al. 2012)

3-    Helps in mitochondrial DNA repair

Deoxyribonucleic acid (DNA) is a unique molecule that contains the genetic blueprint of life. It instructs our body to make essential proteins that are required for our growth and development.

Mitochondrial are the only structures that have their own circular double-stranded DNA (mt DNA). That's why they are known as the cells within the cell.

However, the integrity of the mitochondrial DNA is always under attack from environmental insults like radiation, drugs, viruses, and free radicals. The mtDNA is not an inert material and is subject to extensive mutations during DNA replication. Scientists have estimated that our DNA experiences up to one million mutations in a single day. (Lodish et al. 2008) If these mutations are not repaired, these changes accumulate over time, and the function of many important genes is lost. DNA changes cause aging, cancer, and many genetic diseases.

Nature has devised a sophisticated mechanism to tackle the threat caused by DNA damage, referred to as DNA damage response. This system has many checkpoints that prevent damaging DNA and instantly repair any DNA damage that evades the checkpoints. NAD+ is a key component of the DNA damage response and plays a key role in protecting mtDNA.(Li and Sauve 2015)

4-    Increased Expression of Prohibitants:

Prohibitants are a family of "stress response proteins" that sense mitochondrial stress and help regeneration. They are strategically placed in the inner membrane of the mitochondria so that they can have a close look at what is happening with the mitochondria.

Prohibitan level decreases with the aging process; that's why they are known as longevity assurance proteins.

 Studies have confirmed that Nicotinamide administration increased the expression of prohibitants that help in mitochondrial regeneration. (Coates et al. 1997)

5-    Activation of PARPs pathway

Poly (ADP-ribose) polymerase 1 (PARP-1) is a family of enzymes that are involved in different cellular processes like programmed cell death, DNA repair, and genomic stability. This enzyme uses NAD+ as a substrate to perform its functions.

The PARP pathway is very important for all cells as this is involved in the repair and regeneration of all cells, including mitochondria. It detects any damage occurring at the DNA level and initiates the repair and regeneration process.

When the PARPs pathway is activated, cell death is reduced, and life span increases. As this pathway consumes NAD+, its level can be depleted when the PARP enzyme functions actively. (Goody and Henry 2018) If you want to read more about the causes, consequences, and treatment of NAD+ deficiency, check out this great article, An Introduction to NAD+ Deficiency.

Depleting NAD will halt this enzyme's functioning and result in increased cell death and loss of mitochondrial function. So we will have to replete the NAD level in the body to continue enjoying the benefits. The level of NAD can be increased naturally or through supplementations. Read more about What boosts NAD level naturally.

Take-Home Message:

Maintaining an optimum level of high-quality mitochondria is essential to sustain life. NAD fuels the mitochondria and helps perform its function. NAD supplementation can preserve mitochondrial function by delaying aging and speeding up regeneration.

References:

Cantó, Carles, Riekelt H Houtkooper, Eija Pirinen, Dou Y Youn, Maaike H Oosterveer, Yana Cen, Pablo J Fernandez-Marcos, et al. 2012. "The NAD(+) Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity." Cell Metabolism 15 (6): 838–47. https://doi.org/10.1016/j.cmet.2012.04.022.

Coates, P J, D J Jamieson, K Smart, A R Prescott, and P A Hall. 1997. "The Prohibitin Family of Mitochondrial Proteins Regulate Replicative Lifespan." Current Biology 7 (8): 607–10. https://doi.org/10.1016/S0960-9822(06)00261-2.

Goody, Michelle F, and Clarissa A Henry. 2018. "A Need for NAD+ in Muscle Development, Homeostasis, and Aging." Skeletal Muscle 8 (1): 9. https://doi.org/10.1186/s13395-018-0154-1.

Hongbo, Zhang, Ryu Dongryeol, Wu Yibo, Gariani Karim, Wang Xu, Luan Peiling, D'Amico Davide, et al. 2016. "NAD+ Repletion Improves Mitochondrial and Stem Cell Function and Enhances Life Span in Mice." Science 352 (6292): 1436–43. https://doi.org/10.1126/science.aaf2693.

Li, Wei, and Anthony A Sauve. 2015. "NAD+ Content and Its Role in Mitochondria BT  - Mitochondrial Regulation: Methods and Protocols." In , edited by Carlos M Palmeira and Anabela P Rolo, 39–48. New York, NY: Springer New York. https://doi.org/10.1007/978-1-4939-1875-1_4.

Lodish, U H, H Lodish, A Berk, C A Kaiser, C Kaiser, M Krieger, U C A Kaiser, M P Scott, A Bretscher, and H Ploegh. 2008. Molecular Cell Biology. W. H. Freeman. https://books.google.com.pk/books?id=K3JbjG1JiUMC.

McElroy, Gregory S, Colleen R Reczek, Paul A Reyfman, Divakar S Mithal, Craig M Horbinski, and Navdeep S Chandel. 2020. "NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction." Cell Metabolism 32 (2): 301-308.e6. https://doi.org/10.1016/j.cmet.2020.06.003.