We therefore propose two potential hypotheses describing the reduction in PINK1-mitophagy activity in ALS: a) increased cleavage of PINK1 by PARL (Liu et al, 2023) and/or protein degradation systems (such as UPS and autophagy itself), and b) compromised homeostasis of FL-PINK1 and its different forms (e.g., pathological TDP-43 may impair PINK1 degradation resulting in increased abundance of cytoplasmic cleaved-PINK and compromised mitophagy) (Sun et al, 2018). Here, TARDBP is linked to amyotrophic lateral sclerosis.