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Table 1 Potential mitochondrial targets for neurodegenerative therapy

From: Reappraisal of metabolic dysfunction in neurodegeneration: Focus on mitochondrial function and calcium signaling

Possible mitochondrial targets Function Effect Possible outcome
mtCU-dependent mCa2+ influx MCU inhibitor MCU encodes the channel-forming portion of the mtCU complex, and loss of MCU completely ablates all channel function [71, 72] Reduce mCa2+ uptake Modulation of mtCU dependent mCa2+ uptake mechanisms can reduce pathogenic mCa2+ overload, maintain mitochondrial Ca2+ homeostasis and preserve structure and function
MCUB activator MCUB, a paralog of MCU, exerts a dominant-negative effect and negatively regulates the mtCU by replacing MCU subunits [411]
MICU1 modulator MICU1 prominently regulates the Ca2+ threshold of the mitochondrial calcium uniporter complex (mtCU) [412, 413] and modulates mitochondrial ultrastructure and cristae organization independent of mtCU [414]
  MICU3 modulator MICU3, a brain-specific regulator of mCa2+ uptake, act as an activator at low iCa2+ levels [415]
  EMRE inhibitor EMRE, an essential mtCU regulator and loss of EMRE will reduce overall mtCU formation [416]
mCa2+ efflux NCLX activator A mitochondrial Na+/Ca2+ exchanger acts as a primary route of Ca2+ efflux (3-Na+ in/1-Ca2+ out) (NCLX) [73, 74] Enhance mCa2+ efflux Enhancing mCa2+ efflux can reduce pathogenic mCa2+ overload and its associated mitochondrial dysfunction
mPTP opening Cyclophilin D inhibitor Inhibits mPTP opening and loss of Δψm Reduce cell death Inhibiting mPTP will decrease Ca2+-induced mitochondrial swelling, ROS, and cell death
Complex formation (scaffolds) MICOS stabilizer (Mic10 and Mic60) MICOS is a mitochondrial contact site and cristae organizing system [417] that are regulated by mCa2+ [418] Preserve mitochondrial function Maintaining the MICOS function will preserve respiratory chain complexes, the ATP synthase, mitochondrial architecture, biogenesis, bioenergetics, and function
Proteases m-AAA proteases activator (AFG3L2, paraplegin, YME1L, PARL, HTRA2 m-AAA proteases regulate the assembly of the mitochondrial calcium uniporter complex (mtCU) [419] and OxPhos complex [420] Mitochondrial protein quality control mechanisms and mitochondrial proteostasis Activation of m-AAA proteases will maintain mitochondrial membrane dynamics, axonal transport of mitochondria and can stabilize the mitochondrial genome and the synthesis of mitochondrially encoded subunits of the ETC and preserve mitochondrial morphology
MAMs PDZD8 Inhibitor An ER protein present at ER-mitochondria contacts and required for Ca2+ uptake by mitochondria [219]   Reduced ER-mitochondria Ca2+ transfer could protect against mCa2+ overload mediated cell death