The Care and Feeding of Mitochondria
Ancient little wonders within, releasing energy, processing information, keeping time. Part 1 of 2
Credit: sciencefacts.net
My Mitochondria
No one likes being taken for granted, not even the mitochondria, on which we depend for our biological life, moment to moment. These tiny organelles inhabit every cell of the human body, except for mature red blood cells. They are descendants of bacteria that developed a symbiotic, commensal relationship with eukaryotic cells sometime in the distant past (Bottje, 2018), or at least that is currently the best scientific explanation for their presence and critical function in cells. In view of the fact that hydrogen metabolism is the heart of the electron transport chain, their energy (ATP) generating system, perhaps their ancestors were hydrogen producing bacteria or Archaea? We could use a good Time Machine right about now couldn’t we?
Credit: The Far Side, by Gary Larson
Dr. Lehninger, I Presume?
Dr. Albert L. Lehninger, 1917-1986: Modern Pioneer of Mitochondrial Function and Bioenergetics, and author of the classic textbook: Biochemistry: The Molecular Basis of Cell Structure and Function.
If you had a college biochemistry class between 1970 and 2000 you probably used Lehninger’s Biochemistry as a text book. Maybe not, but it is a true classic, clearly written and logically organized. Dr. Lehninger’s degree in English from Wesleyan University preceded his M.S. and Ph.D., in biochemistry from the University of Wisconsin. He certainly wrote like an English major. He was a professor of Biochemistry at Johns Hopkins Medical School for many years and authored two other textbooks, Mitochondrion and Bioenergetics.
Dr. Lehninger was co-discoverer, with graduate student Eugene Kennedy, of the workings of the electron transport chain in mitochondria, the process by which high energy electrons are used to produce a membrane proton gradient and drive the synthesis of ATP by non other than the enzyme ATP synthase (Neupane et al., 2019). The electron transport chain is part of the engine of life in higher organisms, like ourselves.
Dr. Lehninger made many other important discoveries in bioenergetics and mitochondrial function. I’m not sure why he did not win a Nobel Prize, he should have. One nutritionist’s opinion.
Mitochondrial Statistics: a billion, billion but who’s counting?
Scientists estimate that the human body contains roughly a billion, billion mitochondria, perhaps ten percent of body weight in a person with a normal body mass index. The number of mitochondria varies by cell type in accordance with their activities and energy requirements. Please see below. We can appreciate their importance. Adipocytes (fat cells) have a few hundred mitochondria per cell, except for brown fat cells which can have a few thousand.
Figure credit:
Housed within these elegant cell organelles are the two pillars of oxidative metabolism: The Krebs Cycle (or TCA, tricarboxylic acid cycle), and the electron transport, oxidative phosphorylation chain (ETC) which uses energy-rich NADH and FADH generated by the Krebs cycle to create a proton gradient across the inner mitochondrial membrane (Lehninger, 1975). This proton gradient drives the motor of ATP synthesis, the aptly named ATP synthase complex (ibid). ATP is the energy currency of living cells. Notice below the close spatial relationship between the TCA cycle and the electron transport chain within the mitochondria.
Figure Credit: Martinez-Reyes and Chandel, 2020
ATP: Energy Currency and Signaling
Cells use a lot of ATP. Estimates are that the human body synthesizes 40 to 60 kilograms of ATP per day, with a turnover rate of 10 million molecules of ATP per second (Pizzorno, 2014). Almost inconceivable isn’t it? And it is all orchestrated nearly perfectly. While the overall energy conversion efficiency from glucose to ATP ranges from 40-50 percent the efficiency of the electron transport chain in the mitochondria reaches 80-90 percent (Wilkstrom and Springett, 2020), allowing for some leakage of protons and slippage of the ATP synthase compelex (ibid).
ATP itself is not stored, and so it is in constant motion, cycling between the three sisters of high energy phosphate bonds, ATP, ADP and AMP (Lehninger, 1975). The energy is stored in the bonds between phosphate groups on the right side of the figure.
You may not have been looking for a biochemistry lesson, but it is directly relevant to nutrition. I said that ATP is not stored to any large extent but there is another high energy phosphate compound called creatine phosphate can be stored, largely in muscle. Skeletal and heart muscle act as a bank account for both mitochondria and stored energy. What better reason to exercise your heart and skeletal muscles!
The brain also stores creatine phosphate, using it to replenish ATP to supply the high energy demands of neurons. Creatine is synthesized from the amino acids glycine, arginine and methionine, a fact we will return to in part two.
The Mother Lode: Mitochondrial DNA
In addition to the energy transducing TCA cycle and electron transport chain the mighty mitochondria also contain DNA, referred to as maternal DNA, because it is passed on from the ovum (egg) cell to the fertilized embryo.
Long review papers have been written on this subject but here are a few salient points about mitochondrial DNA:
Mitochondrial DNA is active, not an artifact. Communication exists between nuclear DNA (your 23 pairs of chromosomes) and mitochondrial DNA (Gerhard, 2023). Mitochondrial DNA has even been shown to insert itself into nuclear DNA in brain cells (Picard, 2024). A breakdown in the communication between mitochondria and the nucleus can result in cell dysfunction, senescence and disease, including cancer (Zhang et al., 2022, Martinez-Reyes and Chandel, 2020).
Aging is related to DNA integrity both in the nucleus and the mitochondria. Telomeres are protective “tails” of DNA that slowly decay over time. As they shorten, glitches begin to occur in DNA replication. Disease, toxins and even stress contribute to their loss over time (Yi, et al., 2021, Metcalfe and Ollson, 2021, Monickara et al., 2011).
Reactive oxygen species (ROS) or oxygen free radicals are inevitable byproducts of the electron transport chain and can damage DNA. Cells possess an elaborate network of antioxidant enzymes and produce antioxidant compounds to neutralize these agents. A base level of ROS serve as metabolic signals but excess levels damage cell membranes and DNA. This appears to be related to which step of the ETC the oxygen radicals are generated and whether they end up inside or outside the inner mitochondrial membrane (Bottje, 2018). ROS produced inside the inner mitochondrial membrane can potentially damage the workings of the ETC or mitochondrial DNA, while ROS emitted to the cytosol can act as signals to the rest of cell about how things are going inside the mitochondria (ibid). Amazing.
Mitochondrial DNA can be traced back in time on the maternal side, back to our “Mitochondrial Eve”, who lived somewhere in Northern Africa/Mesopotamia, currently dated to 100 to 150,000 years ago, give or take. This is an entire field of genetic and anthropological study.
Mitochondrial function is related to certain diseases (Zhang et al., 2022) some of which are tied to mitochondrial gene expression. Not surprising is it? Mitochondrial DNA is circular, as in prokaryotic organisms, like bacteria. It contains 37 genes, 13 of which code for enzymes in the electron transport chain, with the rest coding for either transfer RNA or ribosomal RNA both required for protein synthesis (Chadwick, 2025, Martinez-Reyes and Chandel, 2020).
How’s Your Mitochondria Running?
Briefly, there has been some intense searching for a universal blood bio marker for mitochondrial function. To date no stand-alone indicator has emerged, but quite a few bio markers have statistical relationships with mitochondrial function. Most of these are measured in white blood cells and their adjuncts because these cells have mitochondria, while red blood cells do not.
In the late 1960’s biochemist Daniel Atkinson of the University of California proposed the use of the “adenylate energy charge” as a universal indicator of cellular energy status. The adenylate energy charge (AEC) is a ratio based on the concentrations of the three sisters of AMP, ADP and ATP (Atkinson, 1968).
The AEC of the mitochondria and the cytoplasm are essentially equal, and so the idea arose of measuring the AEC of blood cells as a whole body indicator of energy status, and proxy for mitochondrial function. The concept was also applied to microbes. However it has technical limitations in measurement that limited its use. I always was interested in the AEC concept, it made so much sense.
That completes a general overview of the nature and function of mitochondria. In part two of this post we will explore the nutritional needs of mitochondria and how they may be met and perhaps optimized.
Thank you for reading. Part II is in the works.
References
Bottje, W.G. 2019. Oxidative metabolism and efficiency: the delicate balancing act of mitochondria. Poultry Science 98:4223-4230.
Lehninger, A.L., 1975. Biochemistry, 2nd Edition. Worth Publishing.
Martinez-Reyes, I., and N.S. Chandel. 2020. Mitochondrial TCA cycle metabolites control physiology and disease. Nature Comm. 11:102.
Gerhard, D. 2023. Rebranding Mitochondria. The Scientist, Dec. 4, 2023.
Pizzorno, J. 2014. Mitochondria-Fundamental to Life and Health. Integrative Medicine 13:(2). April 2014.
Wikstrom, M., and R. Springett. 2020. Thermodynamic efficiency, reversibility, and degree of coupling in energy conservation by the mitochondrial respiratory chain. Comm. Biology. 3:451
Picard, M. 2024. Mitochondria are flinging their DNA into our brain cells. Columbia Univ. Med. Bull. (www.cuimc.columbia.edu) Aug. 22, 2024.
Zhang, H., Y.F. Chang and J. Liu. 2022. Editorial: Regulation of Mitochondrial Function on Animal Diseases. Frontiers Vet. Sci. 17 June 2022.
Neupane, P., S. Buju, N. Thapa and H.K. Bhattarai. 2019. ATP Synthase: Structure, Function and Inhibition. BioMol Concepts 10:1-10.
Li et., al, 2021. Cancers 13:3842.
Metcalfe, N.B., and M. Olsson. 2021. How telemore dynamics are influenced by the balance between mitochondrial efficiency, reactive oxygen species production and DNA. Molecular Ecology. 00:1-13. (wiley online library.com)
Monickaraj, F., et al., 2012. Accelerated aging as evidenced by increased telomeres shortening and mitochondrial DNA depletion in patients with type 2 Diabetes. Mol. Cell Biochem. 365:343-350.
Atkinson, D.E. 1968. The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry 7:(11) 4030-4034.
Very good question! I don’t know offhand. Perhaps this is the mechanism for toxicity by some antibiotics, depending on dose.
Thank you, that transfer idea is very interesting.