How can you make sure your mitochondria are healthy?
First of all, keeping mitochondrial genes (mtDNA) in optimal condition is a good place to start.
A recent preprint discovered that the shape of the inner mitochondrial membranes (cristae) can promote optimal phase separation of TFAM (Mitochondrial Transcription Factor A), responsible for organizing, compacting, and maintaining the mitochondrial genome (mtDNA) while simultaneously acting as the essential activator for mitochondrial transcription [1,2].The, health and abundance of TFAM directly dictates the stability of the mitochondrial genome, preventing mtDNA degradation and controlling overall copy number [3]
The inner mitochondrial membrane (IMM) that forms the cristae has low curvature/flat, convex surfaces and high-curvature concave surfaces. The authors of the preprint found that these high and low curvature zones serve a different purpose in protecting and promoting the phase separation of TFAM [1] (see diagram below).
➡️ ️ High-curvature zones allow the formation of tightly packed TFAMs. These mature, round, well-formed condensates (see diabgram) serve as structural storage and compaction centers. The high density of these TFAM droplets heavily condenses the mtDNA, which generally represses transcription or sequesters the genome safely.
➡️ ️ Low-curvature zones promote the formation of loosely packed TFANs. Loosely packed TFAM condensates exist in a highly fluid, liquid-like state with rapid molecular exchange. These loosely spread condensates can maintain DNA in an open, relaxed state. Because these TFAMs are loose and less dense, the mtDNA is highly accessible to mitochondrial RNA polymerase (POLRMT) and the replication machinery. The new discovery designates low-curvature zones in the IMM as the primary hubs for active gene transcription and replication. This loose network acts as a molecular "reservoir." When the mitochondrial membrane undergoes remodeling—such as during stress, fusion, or fission—these loose TFAM molecules can rapidly slide, diffuse, or be pulled toward emerging high-curvature spots to form new, stable nucleoids on demand.[1, 4]
The question is, what can mess up your IMM cristae curvatures?
In my 2025 peer-reviewed paper on Neuro-PASC [5], I specifically discussed this topic. Viruses, including SARS-CoV-2, are known to aggressively target the inner mitochondrial membrane (IMM), causing drastic morphological shifts such as "hollow mitochondria" (from cristae destruction/cristolysis) or hyper-fused "elongated mitochondria" (often used as an antiviral defense or a viral metabolic hijack) [5, 6,7].
➡️Hollow Mitochondria (Loss of Cristae Curvature) - In severe infection, SARS-CoV-2 proteins (like Spike or specific ORFs) cause cristolysis—the swelling and unpacking of cristae—leaving the organelle "hollow" and devoid of internal membrane complexity. The complex, highly folded, negative-curvature zones of the cristae are flattened out. The internal architecture reverts entirely to a low-curvature/flat membrane topology. This change imposes devastating effects on how TFMA phase separates:
💥Without high-curvature focal points to act as thermodynamic traps, TFAM cannot transition into tightly packed, mature condensates. The protein remains stuck in its loose, dilute phase.
💥Without high-curvature focal points to act as thermodynamic traps, TFAM cannot transition into tightly packed, mature condensates. The protein remains stuck in its loose, dilute phase.
💥Genomic Instability & Loss: When TFAM cannot tightly pack and shield the mitochondrial genome (mtDNA), the naked mtDNA becomes acutely vulnerable to the massive influx of viral-induced mitochondrial reactive oxygen species (mitoROS). The loose fluid network of TFAM fails to stably anchor the nucleoid to the IMM. This allows loose genetic material to break free. It leaks out of the porous, damaged mitochondrial membrane into the cytosol. Once in the cytosol, this naked mtDNA acts as a Damage-Associated Molecular Pattern (DAMP), binding to cGAS/STING or NLRP3 receptors. This triggers the destructive "cytokine storm" and hyper-inflammation characteristic of severe COVID-19.
➡️Elongated Mitochondria (Hyper-Fusion) - In some phases of cellular stress or specific cell types, mitochondria respond to SARS-CoV-2 by forming hyper-elongated networks. This can occur as a host survival mechanism to maximize ATP generation, or because the virus is inhibiting standard fission (mitophagy) to prevent its own clearance [8]. Elongated tubules feature highly extended, smooth outer and inner boundary membranes (low curvature lengthwise), but maintain tightly compressed, dense parallel cristae arrays internally [5].
💥The Effect on TFAM Packing: The thermodynamic balance is heavily skewed. High cristae density creates an overabundance of negative-curvature anchors, forcing a massive shift toward hyper-tightly packed TFAM condensates. This leads to:
❌Transcriptional Silencing ("Energy Drought"): Because the cristae force an excess of TFAM into ultra-dense, tightly wound condensates, the genetic material becomes too compacted. Mitochondrial RNA polymerase (POLRMT) cannot physically access the promoters. This effectively halts the transcription of crucial Electron Transport Chain (ETC) components, leading to the metabolic "energy outages" linked to Long COVID fatigue.
❌Impaired Segregation: To split and share genetic material properly during cell division or mitochondrial maintenance, nucleoids rely on the loose dynamic pooling of TFAM to slide apart. Hyper-compaction freezes the nucleoids in place. They lock together along the elongated network, preventing proper genome distribution and causing uneven genetic suppression across the cell [9].
If your IMM cristae is not optimal (for whatever reasons), what can be done to restore membrane health and function?
In 2021, my first peer-reviewed paper on melatonin regulation of phase separation in neurodegenerative disorders discussed in great depth and detail, how melatonin can protect membrane health in mitochondria [10].
❤️ Essentially, melatonin protects the structural health of the inner mitochondrial membrane (IMM) cristae curvatures through three primary biophysical mechanisms:
1. Preserving Cardiolipin and Spontaneous Negative Membrane Curvature - Cristae invaginations are highly curved, tubular lipid structures whose geometry is physically stabilized by cardiolipin (CL). Cardiolipin is a unique, cone-shaped, anionic lipid with four acyl chains that naturally concentrates in membrane domains with strong negative curvature, such as the curved apex of IMM cristae.
🔝Melatonin acts as an Interfacial Shield: Melatonin is uncharged across the entire pH range, allowing it to easily penetrate and accumulate within hydrophobic membrane regions. Because it possesses both hydrophilic and lipophilic properties, melatonin localizes preferentially at the hydrophilic/hydrophobic membrane interface. From this exact position, melatonin and its metabolite cascade directly scavenge free radicals before they can abstract hydrogen from cardiolipin's double bonds. By halting this oxidation, melatonin preserves cardiolipin's conical shape, maintaining the spontaneous negative curvature and bending elasticity of the IMM cristae.
2. Maintaining Line Tension - Line tension plays a fundamental role in maintaining the high-curvature geometry of inner mitochondrial membrane (IMM) cristae invaginations by acting as a biophysical regulator of lipid domain boundaries. When the membrane is subjected to oxidative stress, lipid peroxidation alters the molecular structure of lipids like cardiolipin, diminishing the membrane's spontaneous negative curvature and elasticity. As curvature is lost, the line tension at phase boundaries increases significantly (often in the order of several piconewtons). The Outcome: This elevated line tension acts as a physical force that drives smaller, highly curved nanoscopic domains to coalesce. To minimize the energy penalty of the boundaries, the lipids merge into massive, flattened, or distorted macroscopic structures (reminiscent of the transition from nanorafts to micron-sized "inflammarafts"). This flattening directly destroys the dynamic, tightly curved tubular structures of the cristae invaginations.
🔝Melatonin directly counters this destabilization by accumulating at the hydrophilic/hydrophobic membrane interfaces. By intercalating between lipid headgroups and modifying lipid hydrocarbon chain order, melatonin stabilizes the phase boundaries and reduces line tension. It essentially acts as a biophysical surfactant at the phase interfaces, preventing the thermodynamic collapse and coalescence of high-curvature lipid domains even under thermal or oxidative stress.
❤️ The adequate presence of melatonin in mitochondria allows the cristae to maintain their narrow, highly curved, and asymmetrical membrane invaginations. With this balanced high and low curvature architecture, TFAMs are able to protect the mitochondria genome in the most optimal manner.
[1] Hu, X., Shu, L., Zhang, G., Jiang, Y., Yin, Y., Xu, Y., et al. (2026). Curvature-mediated prewetting organize mitochondrial nucleoid. bioRxiv, 2026.04.06.716811. doi: 10.64898/2026.04.06.716811
[2] Ngo HB, Kaiser JT, Chan DC. The mitochondrial transcription and packaging factor Tfam imposes a U-turn on mitochondrial DNA. Nat Struct Mol Biol. 2011;18(11):1290-1296. Published 2011 Oct 30. doi:10.1038/nsmb.2159
[3] Ekstrand, Mats I., et al. "Mitochondrial transcription factor A regulates mtDNA copy number in mammals." Human molecular genetics 13.9 (2004): 935-944.
[4] Ngo, H. B., Lovely, G. A., Phillips, R., & Chan, D. C. (2014). Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nature communications, 5, 3077. https://doi.org/10.1038/ncomms4077
[5] Loh D, Reiter RJ. Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids. Explor Neurosci. 2025;4:100678. https://doi.org/10.37349/en.2025.100678
[6] Bhowal, C., Ghosh, S., Ghatak, D., & De, R. (2023). Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight. Molecular and cellular biochemistry, 478(6), 1325–1343. https://doi.org/10.1007/s11010-022-04593-z
[7] Chen, T.-H., Jeng, T.-H., Lee, M.-Y., Wang, H.-C., Tsai, K.-F., and Chou, C.-K. (2025). Viral mitochondriopathy in COVID-19. Redox Biol. 85, 103766. doi: 10.1016/j.redox.2025.103766
[8] Refrigeri, M., Tola, A., Mogavero, R., Pietracupa, M. M., Gionta, G., & Scatena, R. (2025). Mechanisms of Mitochondrial Impairment by SARS-CoV-2 Proteins: A Nexus of Pathogenesis with Significant Biochemical and Clinical Implications. International journal of molecular sciences, 26(20), 9885. https://doi.org/10.3390/ijms26209885
[8] Ryu KW, Fung TS, Baker DC, Saoi M, Park J, Febres-Aldana CA, et al. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature. 2024;635:746–54.
[9] Gottschalk, C. G., Peterson, D., Armstrong, J., Knox, K., & Roy, A. (2023). Potential molecular mechanisms of chronic fatigue in long haul COVID and other viral diseases. Infectious agents and cancer, 18(1), 7. https://doi.org/10.1186/s13027-023-00485-z
[10] Loh, D.; Reiter, R. J. Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders. Antioxidants (Basel) 2021, 10 (9). https://doi.org/10.3390/antiox10091483.
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