Table 3.

Treatments based on improving mitochondrial function in ALS.

Targets\Drugs	Result of Malfunction	Therapeutic Directions\Therapeutic Efficacy	References
Grxs	The verexpression of Grxs1 in IMS may accelerate mitochondrial fragmentation.	The overexpression of Grx2 interferes with mitochondrial fragmentation, preserves mitochondrial function, and protects neuronal cells from apoptosis.	[40]
OPTN and TBK1	The loss of OPTN or TBK1 function results in impaired mitochondrial phagocytosis and the accumulation of damaged mitochondria.	The binding of OPTN to the ALS-associated E478G ubiquitin prevented stable binding of the mutant to the mitochondrial surface. Furthermore, the recruitment of OPTN and LC3B to damaged mitochondria was significantly reduced using ALS-associated TBK1 mutants.	[50]
C9orf72	C9orf72 haploinsufficiency destabilizes mitochondrial complex I and drives motor neuron degeneration.	Maintaining the integrity of mitochondrial morphology protects C9orf72 from damage, which in turn reduces neuronal degeneration.	[53]
mtDNA	The accumulation of mtDNA mutations leads to increased oxidative damage, decreased energy production, and increased ROS.	Controlling the amount of ROS production and improving the correctness of replication and repair mechanisms may be a potential therapeutic mechanism.	[77]
Nrf2	The loss of Nrf2 accelerates motor neuron death and astrocyte activation, leading to early onset of the disease.	Mutations in the SOD1 gene lead to reduce Nrf2, and finding ways to reduce or inhibit SOD1 gene mutations may improve these problems.	[93]
TDP-43	The accumulation of TDP-43 can promote the increase in endoplasmic reticulum stress level, which in turn promotes the activation of apoptosis.	Calcium ions interrupt fine-tuned signaling between the ER and mitochondria and initiate apoptotic signaling cascades, thus serving as a convergence point for multiple upstream perturbations of cellular homeostasis and constituting a potentially important therapeutic target.	[95]
VBIT-4	mtDNA is a key signaling molecule that triggers inflammatory responses.	Reduced mtDNA release and inflammatory response with VDAC1 oligomerization inhibitor VBIT-4 may offer a potential treatment for ALS.	[100]
Hydroxocobalamin	TDP-43 toxicity impairs mitochondrial function.	Hydroxocobalamin attenuated TDP-43 toxicity, decreased OS and mitochondrial dysfunction, and combined treatment with a low-sugar diet significantly improved motor deficits, suggesting that oral hydroxocobalamin may be a TDP-43-based therapeutic intervention for ALS method.	[130]
MitoQ	In SOD1-G93A mice, mitochondrial function was significantly decreased in spinal cord and muscle, and spinal cord nitrification markers and pathological symptoms were significantly increased.	MitoQ treatment of SOD1-G93A mice slowed the rate of decline in mitochondrial function in the spinal cord and quadriceps, restored muscle connectivity and significantly increased lifespan in mice.	[131]
GNX4728	Changes in mitochondrial membrane permeability affect Ca2+ buffering capacity, which in turn affects mitochondrial metabolism and OXPHOS.	GNX4728 is a regulator of mitochondrial membrane permeability and increases mitochondrial calcium retention via mPTP.	[132]
SHED-CM	Mutations in the SOD1 gene are neurotoxic and induce intracellular aggregation.	Stem cells from SHED-CM can significantly inhibit the intracellular aggregation and neurotoxicity induced by mutant SOD1, have a protective effect on MN, and can be considered as a potential therapeutic approach to slow down the progression of ALS.	[137]
HEXA-018	OS induces neurotoxicity.	HEXA-018 increased the LC3-I/II ratio and increased the number of autophagolysosomes, while also significantly reducing damage to the ubiquitin-proteasome system and oxidative stress-induced neurotoxicity. This suggests that HEXA-018 could be a candidate for ALS treatment.	[138]
Respiratory chain complex	The inhibition of respiratory chain complex activity results in increased ROS production and decreased ATP production.	Cysteine peptide rT1 can promote ATP synthase and cell survival by targeting ETC.	[140]
Double-stranded DNA deaminase toxin A (DddA)	The mutation of mtDNA causes normal mitochondria to gradually die, resulting in abnormal mitochondrial function.	DddA potentially corrects highly pure and specific pathogenic mutations in mtDNA, a highly innovative therapeutic approach.	[141]
triphenylphosphine cation (TPP)	Oxidative stress increases ROS production, leading to cellular damage and decreased ETC activity.	TPP can effectively scavenge ROS and reduce oxidative stress, while also transporting functional proteins into mitochondria.	[142]