At least when mitochondria fragment, they get phagocytosed more easily
Doesn’t this happen more often with exercise, fasting, or starvation? Sometimes if the division is asymmetrical, the one with more damaged parts can get degraded
I saw a paper showing that preventing mitochondrial damage is not always a good thing (detrimental effects). Mitochondria have a life of their own - dynamics VERY different from most other cell parts and operate more like bacteria where evolutionary pressures can make the more robust ones crowd out the less robust ones if you increase selection pressure - and mitodamage IS a selection pressure
Another paper
https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(24)00031-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0968000424000318%3Fshowall%3Dtrue
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Do you have a link to this paper. I would think protecting mtDNA was good.
Lymecycline induces mitostress and is pro longevity
Not due to selection pressure, but due to stress signalling.
Exercise/PGC1alpha increase mitofission right?
CR increases mitofission right?
Parkin does, right?
the relationship is NOT always clearcut
In essence, what the authors did in dFBNs (the glutamatergic “sleep‑control” neurons that project to the dorsal fan‑shaped body in Drosophila) was to take the core fusion/fission machinery—Drp1 (fission), Marf (mitofusin), and Opa1 (inner‑membrane fusion)—and push it one way or the other:
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Driving fission (↑Drp1 or ↓Opa1/Marf)
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Sleep ↓, both in total daily sleep and in the rebound after deprivation.
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Homeostatic sleep pressure (the ability to increase sleep after being kept awake) is abolished.
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ATP in dFBNs ↓ regardless of sleep history.
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Neuronal excitability falls: Drp1‑overexpressing dFBNs fire fewer spikes in response to current (a “shallower” I–F curve). (Nature)
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Driving fusion (↑Opa1 ± Marf or ↓Drp1)
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Sleep ↑, both baseline and rebound.
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Arousal threshold ↑ (flies are harder to wake).
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ATP in dFBNs ↑ (they’re better supplied for the same activity).
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Neuronal excitability rises: Opa1/Marf‑overexpressing dFBNs generate more somnogenic bursts. (Nature)
Crucially, these effects are cell‑type specific—the same manipulations in projection neurons or Kenyon cells do not alter sleep—which pinpoints dFBN mitochondrial form as a direct lever on sleep homeostasis rather than a general neurodevelopmental or toxicity artifact. (Nature)
Does calorie restriction promote mitochondrial fusion / Opa1 up‑regulation?
The answer is: it depends on tissue and context.
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In mouse hepatocytes subjected to 40 % caloric restriction for 6 months, Drp1 and Fis1 (fission markers) actually increased, whereas the core fusion proteins Mfn1, Mfn2 and Opa1 showed no change. (PubMed )
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By contrast, in rodent skeletal muscle CR combined with resistance training led to elevated levels of Opa1 and Mfn1, linking fusion machinery up‑regulation to improved muscle mitochondrial function under energy limitation plus demand. (Physiology Journals)
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More broadly, CR often enhances mitochondrial biogenesis and coupling efficiency (via PGC‑1α, SIRT3, etc.), but its direct effects on the balance of fission versus fusion proteins are tissue‑ and stimulus‑specific—fusion is not a universal signature of CR in every cell type.
Take‑home
- In sleep‑control neurons, tipping mitochondrial shape toward fission or fusion has opposite, predictable effects on sleep and neuronal excitability.
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Calorie restriction does remodel mitochondrial networks, but it doesn’t uniformly up‑regulate Opa1 across all tissues—some cells (e.g., muscle under load) boost fusion proteins, while others (e.g., liver) may actually lean toward fission or show no change in Opa1.
Overexpressing Drp1 vs. Opa1 has very different—and almost opposite—effects on mitochondrial form and cell health:
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Drp1 overexpression (“forced fission”)
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Mitochondrial fragmentation: Drp1 OE drives excessive division, yielding a network of small, punctate mitochondria.
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Oxidative stress ↑: Fragmented mitochondria leak more electrons to O₂, boosting ROS production (Wikipedia).
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Respiratory dysfunction: Excess fission lowers coupling efficiency and OXPHOS capacity, so ATP synthesis falls and cells become more susceptible to apoptosis.
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Cell viability ↓: Many cell types undergo apoptotic or necrotic death if Drp1 stays high (Wikipedia).
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Opa1 overexpression (“forced fusion”)
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Mitochondrial elongation and cristae tightening: Opa1 OE promotes inner‑membrane fusion and preserves cristae architecture.
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ROS ↓: Fused networks maintain a more even membrane potential, reducing the sites for electron leak.
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Respiratory boost: Better cristae structure increases the local density of ATP‑synthase and respiratory supercomplexes, improving ATP output.
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Cell protection ↑: Opa1 OE protects against apoptotic cytochrome c release and preserves viability under stress (Wikipedia).
Bottom line:
Overexpressing Drp1 (fission) is far more deleterious—raising ROS, collapsing ATP synthesis and triggering cell death—whereas overexpressing Opa1 (fusion) generally enhances mitochondrial function, lowers oxidative stress and promotes cell survival.
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Calorie restriction does engage the fission machinery—but not as a simple, uniform “↑Drp1 = ↑fission” across every tissue or age. Instead, CR appears to dynamically modulate mitochondrial shape to first prime fission‑mediated clearance of damaged organelles and then favor fusion‑driven network integrity.
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CR‑driven fission for mitophagy
- In aged liver, CR promotes cardiolipin redistribution that is linked to Drp1‑mediated fragmentation and subsequent autophagy of oxidized membranes (PubMed ).
- A midlife, transient Drp1 pulse in Drosophila mimics CR’s rejuvenating effects—driving fission to clear dysfunctional mitochondria and extending lifespan (Nature).
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CR‑dependent anti‑aging “fine‑tuning”
- In oxidative (soleus) muscle fibers, aging up‑regulates Drp1 (and Fis1) → fragmentation; CR attenuates that rise and actually boosts Mfn2 (fusion) to preserve network integrity (Frontiers).
- In glycolytic (gastrocnemius) muscle fibers, aging increases both fission and fusion markers; CR again blunts the excessive fission (Fis1) while maintaining balanced Drp1/Mfn2 levels (Frontiers).
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Context matters
- Short‑term CR in otherwise healthy young muscle tends to down‑regulate Drp1 and shift the balance toward fusion (via MFN2 up), improving coupling efficiency and lowering ROS (JSciMed Central).
- In contrast, when there’s pre‑existing damage (aging, high‑fat diet, ischemia), CR or a Drp1 boost can kick‑start the fission/mitophagy axis that rejuvenates the network.
Bottom line:
CR doesn’t simply crank up Drp1 everywhere. Rather, it orchestrates a “fission pulse” when damaged mitochondria need clearing (often via Drp1‐dependent cardiolipin signalling), then rebalances toward fusion (Opa1/Mfn2) to rebuild a healthy network. Which effect predominates depends on tissue type, age, and metabolic state.
Drp1 sensitizes mitochondria to MPT, whereas Opa1 protects against it.
Drp1 and increased MPT sensitivity
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Drp1 translocation to mitochondria promotes excessive mPTP opening by directly interacting with pore components (BAX, PiC) and inactivating protective factors like HK2 after hypoxia PubMed .
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Overexpression of Drp1 in permeabilized cells lowers the mitochondrial calcium‑retention capacity (mCRC)—a classic assay for MPT sensitivity—so that lower Ca²⁺ loads trigger pore opening ResearchGate.
Opa1 and resistance to MPT
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Opa1 overexpression (particularly the short S‑OPA1 splice form) tightens cristae and reduces ROS, raising the threshold for Ca²⁺‑ or ROS‑induced MPT PMC.
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Opa1 knockout in liver paradoxically induces mitohormesis but nonetheless decreases sensitivity to drug‑ or Ca²⁺‑triggered MPT, protecting against liver injury Nature.
Bottom line
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Driving fission via Drp1 makes mitochondria more prone to permeability‑transition pore opening (lower Ca²⁺ thresholds, higher ROS–driven pore tips).
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Driving fusion via Opa1 does the opposite—stabilizing cristae, reducing electron leak, and raising the resistance of the inner membrane to MPT.
