Table 2.

Genetic markers associated with mitochondrial dysfunction in ALS.

Protein	Location/Coding Sequence	Result of Malfunction
SOD1 [116]	IMS	Mutated SOD1 induces ALS mitochondrial toxicity.
C9orf72 [117]	Non-coding region (GGGGCC)	Poly(GR) in C9ORF72-related ALS impairs mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived MNs.
TDP-43 [118]	TARDBP (chromosome Ip36.2)	Mutant TDP-43 disrupts mitochondrial dynamics, and overexpression of TDP-43 results in abnormal mitochondrial aggregation and loss of normal function, resulting in progressive neuronal loss.
FUS [119]	Nucleus	FUS plays a role in a cascade of nuclear loss of function and increased cytoplasmic functional toxicity in ALS. Furthermore, FUS mutation and subsequent mislocalization to the cytoplasm sequester additional nuclear proteins critical for RNA metabolism, such as motor neuron proteins (SMN), blunting the nuclear activity of these proteins.
VAPB [120]	ER	VAPB depletion induces increased autophagic flux and decreased ATP production, thereby disrupting neuronal ion homeostasis and function.
SigMar-1 [121]	MANs (mitochondria-associated endoplasmic reticulum membranes, MAMs)	Regulates Ca2+ signaling between ER and mitochondria and maintains MAMs structural integrity.
Nrf2 [122]	Leucine zipper transcription factor	Dysfunctions in the Nrf2 result in a loss of redox homeostasis, leading to overload with reactive oxygen/nitrogen species.
TRPM7 [123]	Plasma	TRPM7 isoforms cause oxidative stress by inducing hypoxia-activated cation currents that increase ROS production.
hIGF-1 [124]		Deletion of hIGF-1 induces mitochondrial apoptosis, inhibits normal mitochondrial mitotic phagocytosis, and promotes motor neuron apoptosis.