ALS (MND) and the Mitochondria - what is the evidence that ALS is a mitochondrial disease?

Regular readers of my blog will have seen that I think there is solid evidence that some neurodegenerative diseases such as ALS (MND) and Parkinsons are caused by a deterioration of mitochondrial DNA primarily because of damage by free radicals (Reactive Oxygen Species - ROS) in the cells. This gradually causes the cells to fail to produce the right proteins and the cells stop working.

I think the reason this happens in ALS (MND) and Parkinson's disease is that the cells that suffer are ones which both have a high energy demand, but also make high use of Oxidative Phosphorylation (OxPhos). Hence the mitochondria generate damaging molecules at higher rate which damages the mitochondria at a higher rate than normal. Cells have systems to deal with this, but once it gets to a certain point the deterioration becomes more rapid. Cells in the Central Nervous System have a supply of melatonin via the CerebroSpinal Fluid (CSF) that helps to resist this, but if there is a shortage for some reason then things start going out of balance.

My objective in this post is to look in more detail at ALS (in the UK called Motor Neurone Disease - MND) to see if this hypothesis fits the known facts about the disease. Also to look for what evidence there is that this does not start in the mitochondria (in the sense that it is potentially a failure of endogenous, but extracellular anti-oxidant supply or something similar)

Genetic Causes
Perhaps the first thing to look at is the known genes that provide a higher risk of ALS and consider how those may relate:

• SOD1 - superoxide-dismutase (detoxifies superoxide in cytosol/mitochondria) this is obviously something where a failure to stop ROS can cause a vicious circle of mitochondrial DNA damage.
• C9ORF72 endosomal trafficking and autophagy initiation complexes - a failure in autophagy (mitophagy) will result in further mitochondrial failure.
• OPTN autophagy (mitophagy) receptor and facilitator of axonal mitochondrial transport - again a failure in mitophagy
• TBK1 activates OPTN/NDP52 during autophagy and restrains innate-immune necroptosis - again a failure in mitophagy
• VCP (p97) that extracts ubiquitinated proteins for proteasomal or autophagic disposal - Mutations stall ER-associated degradation and lysophagy - slightly more remote from mitochondria
• UBQLN2 proteasome “shuttle” that escorts misfolded substrates and helps phase-separate stress granules Mutant UBQLN2 loses shuttling, mis-phases, and traps TDP-43, tipping the balance from reversible stress granules to pathogenic inclusions. - no explanation as yet.
• SQSTM1 (p62), CCNF, VALOSIN-containing protein cofactors act in the same degradative network; rarer but mechanistically similar.

  RNA

• TARDBP (TDP-43) binding protein that represses cryptic exons, controls splicing & miRNA biogenesis - splicing is the key pathway through which mtDNA failings change gene expression
• FUS multifunctional RBP that shuttles to stress granules
• ATXN2 (intermediate poly-Q expansions) Expansions ≥ 31 Q amplify TDP-43 toxicity and distort granule dynamics; a strong disease modifier and cause in ~2–5 % of cases.
• TIA1, HNRNPA1/A2B1, MATR3 reinforce the theme that aberrant phase separation and RNA-metabolism failure are central to ALS. - splicing?

  Cytoskeleton / Axonal Transport — “the cell’s railways”

• PFN1 hands actin monomers to formins; essential for growth-cone actin dynamics | ALS variants destabilise PFN1 and blunt actin polymerisation, impairing axon growth/repair. ([nature.com][8]) |
• KIF5A heavy chain that drives anterograde cargo (incl. mitochondria/vesicles) | C-terminal splice-site or missense mutations abolish autoinhibition → hyper-active, aggregate-prone kinesin that jams axonal transport. ([nature.com][9]) |
• TUBA4A, DCTN1, VAPB and DYNectin complex genes* represent additional, rarer hits disrupting microtubule tracks or motor–cargo coupling.
• TARDffff

  DNA-Damage Response, Cilia & Organelle Integrity — “maintenance crew”

• NEK1 Ser/Thr kinase that partners with C21ORF2 in DNA-repair and primary-cilia length control | Loss-of-function alleles leave motor neurones with unrepaired DNA double-strand breaks and ciliary signalling defects.
• C21ORF2 Interacts with NEK1; reinforces DNA-repair and mitochondrial metabolism | ALS variants destabilise the complex, recreating NEK1-like defects. ([pubmed.ncbi.nlm.nih.gov][11]) |
• CHCHD10 Mitochondrial cristae-junction protein | Mutant protein aggregates within the inter-membrane space, triggering a mitochondrial integrated-stress response and selective motor-neuron death; ultra-rare but fully penetrant. ([alsnewstoday.com][12]) |
• SIGMAR1, ALS2 (alsin) alter ER-mitochondria contacts, endolysosomal pH, or vesicle fusion, each illustrating that organelle-stress alone can initiate the ALS cascade. |
• KIF5A

| Putting it together
More than 40 genes can cause ALS, yet they funnel into five intersecting pathways:

1. Proteostasis collapse(misfolding, impaired autophagy/UPS)
2. Aberrant phase-separation & RNA dys-metabolism
3. Cytoskeletal and trafficking failure
4. Energetics & organelle crosstalk (mitochondria–ER–lysosome)
5. Faulty DNA-damage repair & inflammatory signalling

Conclusion
Because failures of mitochondria drive a number of changes in gene expression it is hard to be completely certain what causes what without experiment, but in a broader sense I think the above is compatible with the idea that at the core of ALS/MND is mitochondrial function failures.

Some relevant links
Recent Progress of Antisense Oligonucleotide Therapy for ALS
Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive ...
Optineurin-facilitated axonal mitochondria delivery promotes neuroprotection and axon regeneration | Nature Communications
TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models | Cell Death Discovery
Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and ...
Analysis of translatomic changes in the Ubqln2 P497S model of ALS ...
Frontiers | Recent progress of the genetics of amyotrophic lateral sclerosis and challenges of gene therapy
ALS-causing mutations in profilin-1 alter its conformational dynamics
Altered molecular and cellular mechanisms in KIF5A-associated ...
The genetics of amyotrophic lateral sclerosis - LWW
ALS-associated C21ORF2 variant disrupts DNA damage repair ...
Silence ALS treats 9 patients' ultra-rare ALS caused by CHCHD10...


I have used chatGPT for searching these details and the session is linked below. This will give references to further information. Obviously the chances are also that there are some errors. However, the general principle appears solid when considering published reviews.

Link to chatGPT sources