Mitochondria

mitochondrial efficiency overview by gpt-5-mini

mitochondria injection https://www.mitrix.bio/ "In these tests, “young” highly functional mitochondria are grown in prototype bioreactors and transfused into the bloodstream. Cells absorb them to help supplement old, dysfunctional mitochondria and reverse energetic decline. These tests showed apparent age reversal in multiple endpoints in animal disease models in-vivo and human cells in-vitro."

mitochondrial donation during IVF: https://undark.org/2016/12/23/three-parent-babies-battle-mitochondria/

"Oocytes contain hundreds of thousands of mitochondria. During early embryogenesis mitochondria are 1) diluted across rapidly dividing cells. 2) transcriptionally silent thereby limiting ROS damage during cleavage. Also damaged mitochondria are subjected to mitophagy." someone ought to add a whole bunch of extra mitochondria and see if that helps with embryo bisection round limits (the artificial twinning human cloning technique). If you add 4x mitochondria, can you bisect 4x as many times?

mitochondrial replacement therapy, various aubrey de grey mitochondria stuff (mitoSENS)

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan (2022)

"Protofection is the transfection of foreign mitochondrial DNA into the mitochondria of all cells in a tissue to supplement or replace the native mitochondrial DNA already present." from https://en.wikipedia.org/wiki/Protofection

http://www.fightaging.org/archives/2010/09/paths-to-the-development-of-mitochondrially-targeted-antioxidants.php

"So have there been free-floating mitochondria in the blood all along, and we're just finally noticing them?" https://blogs.sciencemag.org/pipeline/archives/2020/02/03/free-floating-mitochondria

"interval hypoxia hyperoxia therapy" 1 hour sessions for training your mitochondria https://fit4life.ch/ihht/wissen/

mitochondria doping?

Mitochondrial origins of the pressure to sleep

random mitochondrion facts that may be important for health

  • cardiolipin (diphosphatidylglycerol) is 20% of the inner membrane
  • cardiolipin is composed of 18:2 in SAD americans and other livestock, but 22:6 is preferentially utilized
    • conjugated linoleic acid (trans omega-6) increases apoptotic signaling, perhaps by changing its composition. cancer protection
  • lipid peroxidation can increase proton leak rate and reduce efficiency
  • solanine (green potato and tomato) opens permeability transition pore, increasing leak rate
  • mitochondrial leak test by inhibiting ATP synthase (oligomycin) and measuring oxidative activity
  • PINK1/PARKIN control mitophagy
  • Thyroid hormone (T3) increases mitochondrial biogenesis, raises expression of oxidative phosphorylation proteins and uncoupling proteins
  • bezafibrate and other PPAR agonists, AICAR an AMPK activator (not ALCAR), and compounds that activate PGC‑1α indirectly (exercise, sirtuin activators like nicotinamide riboside / NMN for NAD+ boosting) can increase mitochondrial biogenesis

mitochondrial transfer

including spontaneous intercellular mitochondrial transfer.

Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases -- ".. Intercellular mitochondrial transfer can occur through tunnelling nanotubes (TNTs), extracellular vesicles (EVs) (such as cell-secreted nanobodies including exosomes, microvesicles, and apoptotic bodies), and gap junction channels (GJCs)." This article has some good references for each phenomenon.

can mitochondrion be transferred via contractile injection systems? what about mitochondrion transfer via trogocytosis? possibly requires membrane-bound mitochondrion.

possibly other mitochondrion transfer techniques include cell fusion, fusogens, cell-cell fusion, neurite fusion, axon fusion, dendrite fusion, various membranous bridges, conjugative pilus, .... Some of these can probably be programmed via cell-specific targeting as a form of cell therapy for cell-targeted mitochondrial injection.

Program or enhance TNT-mediated mitochondrial transfer

  • Miro1 (Rho-GTPase) Ahmad et al., EMBO J (2014). Overexpressing Miro1 in mesenchymal stem cells (MSCs) markedly increases intercellular mitochondrial transfer (largely via TNTs) and improves rescue efficacy in injury models; Miro1 knockdown impairs it. EMBO Press Babenko et al., (2018). Extends this: Miro1-high donor cells donate mitochondria more efficiently and improve recovery after experimental stroke. PMC Reviews cementing the mechanism and its use in MSCs/epithelium: Las & Shirihai (2014) and later syntheses. PMC

  • Building more “highways” with M-Sec/TNFAIP2. M-Sec discovery/mechanism. M-Sec (TNFAIP2) induces TNTs in cooperation with RalA and the exocyst; N-terminal polybasic region binds PIP2 to localize at the plasma membrane during TNT initiation. Overexpression increases TNTs; depletion reduces them. PMC, Nature Functional outcome. In podocytes, M-Sec–dependent TNTs are required for mitochondrial transfer; knockout/knockdown diminishes transfer and exacerbates injury. PMC

  • A recent “platform” example in immunotherapy. Baldwin et al., Cell (2024). Bone-marrow stromal cells form nanotubes to CD8⁺ T cells and deliver mitochondria, boosting T-cell metabolic fitness and antitumor efficacy, and positioning TNT-mediated donation as an engineerable therapeutic modality. PubMed, Cell

  • Dialing transfer up/down by cytoskeletal regulators. Down-regulating MICAL2PV (an actin/methionine oxidase splice variant) increases TNT-mediated mitochondrial transfer; the splice form normally suppresses TNT formation. EMBO Press

How to localize/bind mitochondria to TNTs

Key idea: TNTs are mostly F-actin–based (some thicker ones also contain microtubules). To bias mitochondria into TNTs, you attach motors/adaptors on mitochondria that bind actin or microtubules, and/or you enrich TNT-forming proteins at the membrane.

  • Actin-based coupling (into classic thin TNTs): • Myo19 is an OMM-associated myosin that processively transports mitochondria on actin—a direct mechanical link to F-actin inside TNTs. (Great for “loading” mito onto actin tracks.) PMC • Miro1/2 recruit Myo19 to mitochondria; Miro proteins are bona fide OMM receptors coordinating actin- and microtubule-based mitochondrial movement. PubMed • Spire1C (mitoSPIRE1) anchors to mitochondria and nucleates actin on the OMM—strengthening mito–actin contacts that favor entry/retention in actin-rich TNTs. PMC, PubMed • Myo10 (unconventional myosin X) promotes TNT formation; boosting Myo10 increases TNT occurrence and vesicle/organelle transport within them (useful for “making more tracks”). The Company of Biologists, PMC

  • Microtubule-based coupling (useful in thicker TNTs that contain MTs): • TRAK1/2 adaptors + KIF5 (kinesin-1) link mitochondria to microtubules. TRAK1 enhances KIF5B processivity, enabling long-range mito transport—relevant for wider, MT-containing TNTs. Nature • Direct evidence that mitochondria ride microtubules inside intercellular nanotubes exists in cell models, supporting the MT-coupling route when tube caliber allows. PMC

  • Programmable/tunable tethers you can adapt for TNTs (toolbox papers): • Chemically inducible dimerization (CID) lets you tether mitochondria to chosen structures on demand (rapamycin FKBP–FRB; also split-FRB variants). Prior work shows inducible ER–mitochondria and PM–mitochondria contacts using TOM20-FRB + organelle- or membrane-anchored FKBP—a template you could adapt by fusing FKBP to a TNT-enriched protein (e.g., M-Sec or Myo10) to bias mitochondria into TNTs. PMC • ActuAtor (Listeria-inspired) recruits an actin-polymerizing module to user-defined membranes (including mitochondria via TOM20 tags) upon rapamycin, generating local actin forces—handy for “pushing” mitochondria along actin-rich protrusions like TNTs. PMC, BioRxiv

biological mitochondrial transfer techniques

  • To program donors to donate more mitochondria through TNTs: Overexpress Miro1 in donor MSCs or stromal cells; consider co-boosting M-Sec or Myo10 in the network-forming cell type to increase TNT density. EMBO Press, Nature, The Company of Biologists
  • To bias mitochondria into TNTs and keep them there: Enrich Miro1/2–Myo19 on the OMM (for F-actin TNTs) and/or Miro–TRAK–KIF5 (for MT-containing TNTs). PubMed, PMC, Nature
  • To test direct “binding/localization” strategies: Use CID with TOM20-FRB on mitochondria and FKBP-M-Sec or FKBP-Myo10 at TNT membranes to inducibly dock mitochondria to TNTs; verify by live imaging of Mitotracker/PAgfp-mito and line-scan intensity along TNTs. (This leverages established CID organelle-tethering systems.) PMC

Separately, mitochondria can be transferred via direct injection.

intramitochondrial parasitism

also there is at least one intramitochondrial endosymbiont called "Midichloria mitochondrii" and it resides in the mitochondria of hard tick (Ixodes ricinus) oocytes.

mitochondria and longevity

mitochondrion membrane "peroxidizability" is lower in long-lived species. Across mammals (incl. humans) and birds, mitochondrial phospholipids have fewer highly polyunsaturated fatty acids (esp. DHA) → membranes are harder to oxidize, lipid peroxidation is lower, and mitochondria age more slowly. Humans fall on the "low peroxidizability" end vs mice. Naked mole-rats and many birds are extreme examples

mtDNA mutations scale with lifespan. get good at mtDNA repair or mitophagy. or mitochondrial replacement therapies somehow.

antioxidant/repair capacity or location may track longevity better than raw ROS production. (ref)

bats have enhanced mitophagy/DNA-damage responses and a dampened NLRP3 inflammasome, reducing mito-inflammation during stress (flight). (ref)

human mitochondria have lower PUFA content and a lower peroxidation index than mice.

naked mole rats mitochondrial membranes are unusually resistant to peroxidation (very low DHA in phospholipids).

human oocyte mitochondria seem to be uniquely protected. (ref)

TODO: look for human mitochondrial longevity mutations in the literature.

mtDNA copy number (mtDNA-CN) should be increased (ref)

MitoSENS: mitochondria DNA mutations need to be bypassed (MitoSENS) by moving mtDNA genes to the nucleus (allotopic expression) and import the proteins back into mitochondria to maintain cellular respiration. Allotopic expression of mitochondrial genes into the nucleus will require recoding for cytosolic translation and also mitochondrial targeting sequences. Mitochondrial-targeted nucleases could be used to eliminate mutant genomes. Therapeutic mitochondrial transplantation or progenitor cell transfer. Engineer enhanced mitochondrial import machinery. Add mitochondrial-targeted DNA repair systems. Overexpress mitochondrial biogenesis factors (PGC-1α, NRF1/2).

dec2P384R enhances mitochondrial respiratory capacity in Drosophila flies and HEK293 cells (ref)

BAM15: Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster

mitochondrial uncouplers sometimes also have a pro-longevity effect.

See also mitochondria.