Mitobolites (Mitochondrial metabolites): The Elixir of Life?

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Mitochondrial metabolites, also known as Mitobolites, are mitochondrial tricarboxylic acid cycle (TCA) metabolites which are intermediate compounds that are found in the citric acid cycle and are necessary to generate cellular energy for tissue fuel.

The citric acid cycle – also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle – is a series of chemical reactions used by all aerobic organisms to generate energy through the oxidation of acetyl-CoA derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of guanosine triphosphate (GTP).

A study from July 2014 published in Cell Metabolism entitled, Mitobolites: The Elixir of Life, reviewed previously published studies that focused on how mitochondrial tricarboxylic acid cycle (TCA) metabolites work to increase lifespan.

The following mitochondrial tricarboxylic acid cycle (TCA) metabolites have been previously shown to extend lifespan upon feeding in C. elegans:

  • Alpha ketoglutarate  1 
  • Fumarate  2 
  • Malate  3 
  • Oxaloacetate  4 
  • Pyruvate  5  

The authors in the study entitled, The metabolite alpha-ketoglutarate extends lifespan by inhibiting the ATP synthase and TOR, reveal  how αlpha-ketoglutarate, a mitochondrial metabolite (mitobolite) inhibits mitochondrial ATPase and extends lifespan by mimicking dietary restriction in worms. 

The authors in the study showed that αlpha-ketoglutarate inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by αlpha-ketoglutarate leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells.  6

These small mitobolites may regulate cellular signaling pathways and result in a number of effects:  7

  • Inhibition of the TOR pathway
  • Increase in autophagy

Beyond the ability of mitobolites to increase lifespan, mitobolites also have shown to have a wide variety of other health benefits.  These additional health benefits are listed in the Table below:

Health Benefits of Mitobolites

Mitobolites  
MitoboliteEffectReferences
Alpha-ketoglutarate
Alpha-Ketoglutarate may protect the Brain and Liver from Cyanide toxicity1
Alpha-Ketoglutarate may help to remove Ammonia from the body2
Alpha-Ketoglutarate may inhibit the ability of Nitrosamines to cause Liver Cancer3
Alpha-Ketoglutarate may increase Muscle Strength4
Alpha-Ketoglutarate (Pyridoxine Alpha-Ketoglutarate (PAK) form - 1,800 mg per day) may enhance the effectiveness of Insulin and Phenformin in Diabetes Mellitus patients (both Diabetes Mellitus Type 1 and Diabetes Mellitus Type 2)5
Malate
The changes in muscle metabolism produced by citrulline/malate (CM) treatment indicate that CM may promote aerobic energy production.6
Malic Acid may increase Stamina and may minimize Muscle damage during Exercise7
Malic Acid may facilitate the excretion (chelation) of Aluminium from the body8
Super Malic, a proprietary tablet containing malic acid (200 mg) and magnesium (50 mg), in treatment of primary fibromyalgia syndrome (FM).9
Oxaloacetate
Oxaloacetate increases energy production. These studies highlight the importance of optimal substrate concentrations in the CO2 release isotopic PDHC method. Higher PDHC activity is found with intact mitochondria and thus activity values should be interpreted in the light of the presence or absence of intact mitochondria in individual preparations.10
Brain neuroprotection by scavenging blood glutamate. We observed highly significant improvements of the neurological status of rats submitted to closed head injury (CHI) following an intravenous treatment with 1 mmol oxaloacetate/100 g rat weight which decreases blood glutamate levels by 40%.11
Oxaloacetate reduces brain trauma. Oxaloacetate restores the long-term potentiation impaired in rat hippocampus CA1 region by 2-vessel occlusion. Our results suggest that oxaloacetate-mediated blood and brain glutamate scavenging contributes to the restoration of the LTP after its impairment by brain ischaemia. 12
Oxaloacetate Feeds and Grows Brain Cells13
Oxaloacetate is known to be a glutamate scavenger The results of this study demonstrate that the primary mechanism by which oxaloacetate provides neuroprotective activity after CHI is related to its blood glutamate scavenging activity.14
Oxaloacetate induces at least a partial mitochondrial biogenesis, reduces inflammation, and may enhance neurogenesis activity and glucose utilization15
Oxaloacetic Acid Supplementation as a Mimic of Calorie Restriction 16
Acute Oxaloacetate Exposure Enhances Resistance to Fatigue in in vitro Mouse Soleus Muscle. These results demonstrate that acute exposure to oxaloacetate increases resistance to fatigue in mouse slow-twitch muscle, and potential sources of this improvement may be due to increased substrate-level phosphorylation within the mitochondria or some other enhancement of the TCA cycle function. 17
Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway18
Acetyl-L-carnitine and oxaloacetate in post-treatment against LTP impairment in a rat ischemia model19
Pyruvate and oxaloacetate limit zinc-induced oxidative HT-22 neuronal cell injury20
The Effect of Blood Glutamate Scavengers Oxaloacetate and Pyruvate on Neurological Outcome in a Rat Model of Subarachnoid Hemorrhage21
The study reviews the recent experimental and clinical results where it is demonstrated the potential applicability of oxaloacetate as a novel and powerful neuroprotective treatment against ischemic stroke.22
Neuroprotective effect of pyruvate and oxaloacetate during pilocarpine induced status epilepticus in rats23
The permeability of mitochondria to oxaloacetate and malate24
Neuroprotective effect of oxaloacetate in a focal brain ischemic model in the rat. These results provide new evidence of the neuroprotective effect of OxAc against ischemic injury, which strengthens the likelihood of its future applicability as a novel neuroprotective agent for the treatment of ischemic stroke patients. 25
Oxaloacetate decreases the infarct size and attenuates the reduction in evoked responses after photothrombotic focal ischemia in the rat cortex. We suggest that the neuroprotective effects of OxAc are due to its blood Glu-scavenging activity, which, by increasing the brain-to-blood Glu efflux, reduces the excess Glu responsible for the anatomical and functional correlates of the ischemia, as evaluated by electrophysiological evoked potential (EP) measurements.26
Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. 27
Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. These results demonstrate that supplementation of the citric acid cycle metabolite, oxaloacetate, influences a longevity pathway, and suggest a tractable means of introducing the health-related benefits of dietary restriction.28
Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. These results suggest that alpha-keto acids such as alpha-ketoglutarate and oxaloacetate play a role in the inhibition of seizures and subsequent mtDNA damage induced by the excitotoxic/neurotoxic agent, kainic acid.29
Studies on the anti-diabetic effect of sodium oxaloacetate.30
Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. The authors demonstrate that the blood glutamate scavengers oxaloacetate and pyruvate provide neuroprotection after traumatic brain injury, expressed both by reduced neuronal loss in the hippocampus and improved neurologic outcomes.31
Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment. In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. 32
Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. 33
MRS of Brain Metabolite Levels Demonstrates the Ability of Scavenging of Excess Brain Glutamate to Protect against Nerve Agent Induced Seizures. Our results show that the administration of recombinant glutamate-oxaloacetate transaminase (rGOT) in combination with oxaloacetate (OxAc) significantly reduces the brain-accumulated levels of glutamate.34
Blood glutamate scavenging as a novel neuroprotective treatment for paraoxon intoxication. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. 35
Pyruvate
Pyruvate may improve Insulin Sensitivity and may reduce Blood Sugar in Diabetes Mellitus Type 236
Pyruvate appeared to reduce the insulin resistance that develops spontaneously in obese rats. 37
ingestion of 6 g of pyruvate for 6 wk, in conjunction with mild physical activity, resulted in a significant decrease in body weight and fat mass.38
Pyruvate (6,000 mg per day) may improve Stamina39

Different forms of supplemental Mitobolites

Each mitobolite has different forms as supplements which are distinguished by their differing function and bioavailability. 

The Table below lists the various forms of each mitobolite:

Forms of Mitobolites

Forms of Mitobolites 
MitoboliteForm
Alpha-ketoglutarate (AKG)
Arginine AKG (also known as AAKG) is a form of AKG that consists of AKG bound to Arginine
Calcium AKG is a form of AKG that consists of AKG bound to Calcium
Creatine AKG is a newly-developed supplemental form of AKG consisting of Creatine bound to Alpha-Ketoglutarate
Magnesium Alpha-Ketoglutarate (also known as Magnesium AKG or Mag-AKG) is a supplemental form of AKG that consists of 87.5% AKG bound to 12.5% Magnesium
Ornithine AKG (OKG) is a supplemental form of AKG that consists of 64% Ornithine bound to 36% Alpha-Ketoglutarate
Potassium Alpha-Ketoglutarate (also known as Potassium AKG or Pot-AKG) is a supplemental form of AKG that consists of 70% AKG bound to 30% Potassium
Pyridoxine AKG (also known as PAK) is a supplemental form of AKG that consists of AKG bound to the Pyridoxine form of Vitamin B6
Fumurate
L-Carnitine Fumarate is fumurate bound to L-carnitine
Malate
Calcium Malate consists of Calcium bound to Malic Acid
DiCalcium Malate consists of 30% Calcium bound to 70% Malic Acid
Citrulline Malate consists of Citrulline bound to Malic Acid
Creatine Malate consists of Creatine bound to Malic Acid
Magnesium Malate consists of 82.5% to 87% Malic Acid bound to Magnesium
DiMagnesium Malate consists of 81% Malic Acid bound to 19% Magnesium
Oxaloacetate
BENAGENE(TM) brand Thermally Stabilized Oxaloacetate
The US Patent and Trademark Office has issued Patent 9,050,306 for the thermal stabilization of oxaloacetate compounds. This thermal stabilization has allowed Benagene(TM) to provide room-temperature oxaloacetate with a shelf-life of over two years
The National Institute on Aging (part of NIH) has selected oxaloacetic acid (benaGeneTM) for long-term testing under the Interventions Testing Program (ITP). NIA's ITP is a multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction. Oxaloacetic acid is in Cohort 4
Pyruvate
Calcium Pyruvate is comprised of 60 - 80% Pyruvic Acid combined with 20 - 40% Calcium
Creatine Pyruvate consists of 60% Creatine bound to 40% Pyruvic Acid
Magnesium Pyruvate consists of Magnesium bound to Pyruvic Acid
Potassium Pyruvate consists of Potassium bound to Pyruvic Acid
Pyruvylglycine consists of Pyruvic Acid bound to Glycine
Sodium Pyruvate consists of Pyruvic Acid bound to Sodium


Resources:*

Alpha-ketoglutarate:

Fumurate:

 Malate:

Oxaloacetate:

Pyruvate:

*  BioFoundations does not endorse any mitobolite supplement, supplement company or retailer, but simply provides a resource to purchase them.


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