Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes

Lang, Martin; Pramstaller, Peter P.; Pichler, Irene

doi:10.1186/s13024-022-00555-7

Molecular Neurodegeneration

Table 1 Summary of descriptions of mitochondria-lysosome crosstalk

From: Crosstalk of organelles in Parkinson’s disease – MiT family transcription factors as central players in signaling pathways connecting mitochondria and lysosomes

Topic	Conclusion	Cell Type/ model	Genetic/ chemical alterations	Ref
Mitophagy	Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential and promotes autophagy of damaged mitochondria	HEK293; HeLa cells; rat cortical neurons; MEFs	overexpression of fluorescently labeled Parkin; Mfn knockouts; CCCP treatment	[47]
Mitophagy	PINK1 signals mitochondrial dysfunction to Parkin, which promotes their degradation	HeLa cells; rat cortical neuron; MEFs	overexpression of fluorescently labeled Parkin and PINK1; PINK1 mutants and knockout; CCCP and rapalog treatment	[48]
Mitophagy	Parkin amplifies PINK1-mediated mitophagy signals to engage specific autophagy receptors	HEK293T; HeLa cells; rat cortical neurons; MEFs	knockout of autophagy receptor genes; overexpression of fluorescently labeled Parkin and PINK1	[51]
Organelle dynamics	Mitochondrial and lysosomal dynamics is regulated bidirectionally at mitochondria-lysosome contact sites	HeLa cells	overexpression of wt and mutant Rab7-GFP	[57]
Organelle dynamics	Mitochondria-lysosome contacts dynamically form in different neuronal cell compartments and participate in organelle regulation	iPSC-derived neurons with GBA1 mutation	TBC1D15 overexpression; GCase inhibition with conduritol-β-epoxide (CBE)	[58]
Organelle dynamics	Autophagosomes originate from ER-mitochondria contact sites	COS7; HeLa; HEK293 cells;	starvation, STX17 knockdown	[59]
Organelle dynamics	Mitochondrial homeostasis is regulated by the endosomal protein sorting machinery	RPE; HeLa cells	EHD1, Rank5 siRNA; staurosporine; GST–EHD1 expression	[60]
Mitochondria-lysosome crosstalk	Inhibition of GCase activity induces defects in mitochondrial function and oxidative stress in vitro	SH-SY5Y cells	long-term CBE treatment; GBA1 knockdown	[70]
Mitochondria-lysosome crosstalk	A primary lysosomal defect due to GBA1 mutations causes accumulation of dysfunctional mitochondria due to impaired autophagy and dysfunctional proteasomal pathways	mouse model of brain Gba1 deficiency; primary neurons	Gba1 het/hom knockout; LC3-GFP; mitochondrial stressors	[72]
Mitochondria-lysosome crosstalk	GCase deficiency leads to aggregation of multiple proteins and abnormal mitochondrial function in vivo	Gaucher Disease mouse model; cortical neural cells	Gba1 mutations + hypomorphic prosaposin mutation; CBE treatment	[73]
Transcriptional feedback loop	Mitochondrial regulation of lysosomes is time- and context dependent	MEFs; human fibroblasts; SK-N-MC cells	Mutations in CI genes; CCCP, rotenone treatment	[64]
Transcriptional feedback loop	AMPK plays a central role in mitochondria-lysosomal crosstalk	HeLa cells; MEFs	UQCRC1, FLCN knockdown; Ndufs4, Prkaa1/2 knockout	[65]
Transcriptional feedback loop	Mitochondrial function is impaired in lysosomal storage disease models	patient fibroblasts; mouse tissues	NPC1- and ASM1-deficiency; ETV1, KLF2 knockdown	[66]
Transcriptional feedback loop	FLCN is a regulator of AMPK and contributes to the integration of energy metabolism and autophagy	C. elegans; MEFs	flcn-1, aak-2 knockdown and mutations; Ampk, Flcn knockout; cellular stressors	[77]
Metabolism	Dysfunctional mitochondria affect microtubule trafficking and lead to defective autophagy in PD	mtDNA-less Rho0 cells; Cybrid cells from Ctrls and PD patients; primary cortical neurons	Serum, pyruvate/uridine starvation, lysosomal proteolysis inhibition; MPP +	[61]
Metabolism	Impaired mitochondrial metabolism affects endolysosomal function in T-cells	mouse T-cells; T-lymphoblasts; Jurkat T cells	Tfam knockdown and knockout; nicotinamide precursor NAM treatment	[62]
Metabolism	Loss of mitochondrial function impairs lysosomal activity in a ROS-dependent manner	mouse cortical neurons; MEFs	knockout of AIF, OPA1, PINK1; OXPHOS complex inhibitors, antioxidant treatment	[63]
Ca²⁺ homeostasis	Similar to mitochondria, lysosomes can selectively accumulate Ca²⁺ and shape intracellular Ca²⁺ signaling	HEK and COS-7 cells	chemical and genetic disruption of lysosomal function	[74]
Ca²⁺ homeostasis	Mitochondria-lysosome contact sites regulate mitochondrial Ca²⁺ dynamics	HeLa, HEK293, HCT116 cells; fibroblasts	TRPML1 agonist ML-SA1 treatment; TRPML1 mutant expression	[75]
Ca²⁺ homeostasis	Lysosomal biogenesis and autophagy are regulated through TFEB in a Ca²⁺/MCOLN1-dependent manner	HeLa cells	PPP3CB (calcineurin subunit) knockdown and overexpression; TFEB-GFP/TFEB-Flag overexpression; starvation	[76]

A list of studies describing the mitochondria-lysosome crosstalk are summarized to reflect the major functional connections between mitochondria and lysosomes outlined in Fig. 1. Main conclusions, study models and genetic manipulations or chemical treatments used to draw conclusions are shown

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ISSN: 1750-1326

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