Mitochondrial Dysfunction and Disorganized Microtubules in Duchenne Muscular Dystrophy are Not Related to Altered α Tubulin‐Voltage Dependent Anion Channel (VDAC) 2 Interactions
Bibliographic record
Abstract
Rationale In Duchenne muscular dystrophy (DMD), a genetic mutation results in a loss of dystrophin which leads to microtubular disorganization, cellular degeneration and muscle weakness. However, a mechanism by which microtubule disorganization contributes to muscle weakness in DMD has not been established. We considered a model that proposes tubulin, the structural component of microtubules, may directly bind VDAC2 on the outer mitochondrial membrane and alter its permeability to ADP import. Given ADP stimulates oxidative phosphorylation and attenuates H 2 O 2 emission through modulation of membrane potential, the model predicts that tubulin‐VDAC interactions may be a novel regulator of cellular energy and redox homeostasis. Furthermore, as VDAC is also thought to be involved in formation of the mitochondrial permeability transition pore (mPTP) in response to calcium stress – a phenomenon that occurs in DMD – tubulin‐VDAC interactions may also influence the maximal mitochondrial calcium retention capacity (CRC) required to trigger cell death. Considering these relationships between VDAC and bioenergetic control, we hypothesized that the disorganized microtubule network in DMD would be linked to impairments in ADP's control of bioenergetics and mPTP formation through altered tubulin‐VDAC binding. Methods Permeabilized fibre bundles and single fibers from 4 week old wildtype (WT) and D2. mdx (DMD mouse) were prepared from extensor digitorum longus (EDL) muscles and used for mitochondrial bioenergetic and histological assessments. Results D2. mdx EDL demonstrated impaired ADP‐stimulated respiration at a range of ADP concentrations (−37–43% at 25mM, 100mM, 500mM and 5mM ADP, p<0.003 ) and an impaired ability of ADP to attenuate H 2 O 2 emission (71% increase in H 2 O 2 at 500mM ADP, p=0.04 ) despite similar CRC. There were no differences in the protein content of electron transport chain complex subunits (Complexes I to V) or VDAC2 despite significantly decreased adenine nucleotide translocase (ANT) ( p=0.03 ). a‐tubulin–VDAC2 interactions were unchanged despite alterations to a‐tubulin network in D2. mdx fibers. Conclusions and Discussion Disorganized microtubules in EDL from D2. mdx mice are related to mitochondrial dysfunction, but this is not due to altered a‐tubulin–VDAC2 interactions. It remains to be determined if interactions between other tubulin or VDAC isoforms are altered in DMD and contribute to impaired VDAC‐dependent bioenergetics. In addition, reduced ANT content may partially explain impaired mitochondrial function in dystrophic EDL. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. S.V.R was supported by Ontario Graduate Scholarship. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".