. 2021 Jul 7;9:124. doi: 10.1186/s40478-021-01224-4

Table 1.

Potential mitochondrial targets for neurodegenerative therapy

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