Mitochondria: Powerhouse of the Cells
Mitochondria are tiny organelles that create every bit of energy our cells need to carry out their functions; such as replication, growth, repair and maintenance.
Mitochondria are amazing structures in many ways. They contain their own set of DNA – known as mitochondrial DNA. They can alter their number to meet the changing energy requirements of the cells. If a cell requires more energy, more mitochondria are created. Some cells have no or limited mitochondria while others may contain hundreds and even thousands of these structures. Our heart, liver, kidney, immune system and brain are loaded with mitochondria as these systems need tremendous amounts of energy.
But it seems there is more to mitochondria than meets the eye. Healthy mitochondrial function is at the very heart of practically every process in the body. Besides being an important part of energy metabolism, these energy factories are also vital for cell survival and help them to deal with all kinds of internal and environmental triggers – such as oxidative stress, DNA damage and nutritional deficiencies.
Mitochondria serve several other cellular functions as well. These include:
- Production of heat
- Storage of calcium ions, which are involved in formation of healthy bones, transmitting nerve impulse, blood clotting, muscle contraction and fertilization. Mitochondria also serve as ‘sinks’ to offset the damage by calcium overload.
- Import of metabolites and energy intermediates
- Serving as the initial production site for various hormones such as cortisol, oestrogen, progesterone and testosterone.
- Making the iron compound that helps red blood cells to transport oxygen to tissues and organs.
Needless to say, the health of mitochondria is extremely important for overall health. While there are many nutrients and precursors that your mitochondria need to be alive and kicking, NAD+ plays an exceptional role here. Fading level of NAD+, common with aging, can cause mitochondrial functions to falter and weaken – giving rise to premature cellular aging and age-related disorders.
NAD+ and Mitochondria
NAD+ or nicotinamide adenine dinucleotide, is a coenzyme involved in cellular energy metabolism and energy production.
Mitochondria process oxygen (that we breathe) and fats and glucose (from the food we eat) to create energy. This process is called oxidative phosphorylation – where electrons are transferred from electron donors to electron acceptors in a highly complicated, ongoing series of redox reactions. Many nutrients (such as magnesium, manganese, CoQ10) are involved in driving this process forward, with each playing its unique and critical role.
Let us focus on NAD+ for the moment.
Oxidation of fuels (fats and glucose) releases electrons. NAD+ accepts these electrons; reducing to NADH in the process.
NADH transfers these electrons in this continuing series of redox reactions. The transfer of electrons release energy, further utilized to pump protons across the inner mitochondrial membrane. This creates a proton gradient across the membrane – eventually leading to the synthesis of ATP, our energy currency. During these mitochondrial pathways, NAD+ keeps alternating between two forms; NAD+ and NADH; crucial for normal oxidative phosphorylation process and generation of ATP. 
Ironically, this vital process also generates by-products such as reactive oxygen species or free radicals – notorious for their role in damaging delicate cellular structures such as lipids, proteins and mitochondrial DNA. The increased oxidative damage to important biological structures is proposed as one of the leading theories behind cellular aging. And aging is not only about wrinkled skin and grey hair. It impairs immunity and causes organs to weaken – leading to many disorders commonly associated with aging. But healthy and well-functioning mitochondria keep a check on this damage inflicted by free radicals.
NAD+, Sirtuins and Mitochondrial Health
There is another important way NAD+ influences the health of our mitochondria.
NAD+ activates sirtuins – specific proteins that are well-known for their role in regulating the process of aging. NAD+ dependent sirtuins enhances metabolic efficiency and help cells develop resistance against oxidative stress; the latter function achieved by enhancing anti-oxidant pathways and facilitating DNA damage repair . All these mechanisms help improve mitochondrial fitness, delay cellular aging and promote longevity.
In short, sirtuins controls how our body responds to metabolism and stress. These are two important mechanisms implicated in the process of aging.  Leading research on sirtuins tells us that these proteins can help delay aging; thus, also slow down the onset as well as the development of age-related pathologies such as arthritis, heart disease, type 2 diabetes, neurodegenerative diseases and cancer.
NAD+ facilitates nucleus-mitochondria communication
The availability of NAD+ and the resulting sirtuins activity also help facilitate communication between the nucleus and mitochondria at a cellular level. Now, reduction in NAD+ levels also disrupts the nuclear-mitochondrial connection, further weakening mitochondria. 
Dr. David Sinclair, Harvard Medical School Professor of Genetics commented that “this communication network is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down. And just like with a couple, restoring communication solved the problem.” In other words, improving the intercellular communication can help slow down aging and improve overall health.
Role of NAD+ in maintaining mitochondrial health
NAD+ levels in the body decline with age. Overeating and leading a sedentary lifestyle also depletes NAD+ levels. While sirtuins need NAD+ to carry out its functions, there are some other classes of proteins – more specifically Poly-ADP-ribose Polymerases (PARPs) and CD38 – that also rely on the same NAD+ reservoir in the nucleus. This causes further decline in NAD+ levels.
What does declining levels of NAD+ mean to mitochondria?
- Energy production process within the mitochondria takes a hit (impaired energy metabolism)
- The number and density of the mitochondria are reduced
- There is a reduced activity of sirtuins
All of this impairs the mitochondrial functions, resulting in:
- Reduced energy production; consequently, healthy cellular functions such as replication, growth, repair and maintenance are impaired.
- Failure to respond to stress induced by oxidative damage, lack of nutrition, DNA damage and other stressors. This impacts cell survival.
- Increased generation of reactive oxygen species; causing further oxidative damage. This eventually leads to runaway chronic inflammation, underlying cause of many health conditions.
- Impaired metabolism
As stated in this study , “NAD+ levels decline during the aging process and may be an Achilles’ heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies.”
Given the role of NAD+ and NAD+ dependent sirtuins in mitochondrial functions, NAD+ supplementation could be an effective strategy for reducing mitochondrial damage, hence slowing down the aging process and providing protection from several degenerative diseases caused by aging. This includes all kinds of metabolic disorders such as insulin resistance and type 2 diabetes, neuro-degenerative disorders such Alzheimer’s and Parkinson’s disease, cardiovascular disease and arthritis.
- Other Mitochondrial Functions. Rice University.
- Imai et al. NAD+ and Sirtuins in Aging and Disease. Trends in Cell Biology. 2014.
- Akiko Satoh, Liana Stein, Shin Imai. The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity. Handb Exp Pharmacol. 2011; 206: 125–162.
- Gomes et al. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 2013.