The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering

Abstract

DJ-1 was first identified as an oncogene. More recently, mutations in its gene have been found causative for autosomal recessive familial Parkinson disease. Numerous studies support the DJ-1 role in the protection against oxidative stress and maintenance of mitochondria structure; however, the mechanism of its protective function remains largely unknown. We investigated whether mitochondrial Ca(2+) homeostasis, a key parameter in cell physiology, could be a target for DJ-1 action. Here, we show that DJ-1 modulates mitochondrial Ca(2+) transients induced upon cell stimulation with an 1,4,5-inositol-tris-phosphate agonist by favouring the endoplasmic reticulum (ER)-mitochondria tethering. A reduction of DJ-1 levels results in mitochondria fragmentation and decreased mitochondrial Ca(2+) uptake in stimulated cells. To functionally couple these effects with the well-recognized cytoprotective role of DJ-1, we investigated its action in respect to the tumour suppressor p53. p53 overexpression in HeLa cells impairs their ability to accumulate Ca(2+) in the mitochondrial matrix, causes alteration of the mitochondrial morphology and reduces ER-mitochondria contact sites. Mitochondrial impairments are independent from Drp1 activation, since the co-expression of the dominant negative mutant of Drp1 failed to abolish them. DJ-1 overexpression prevents these alterations by re-establishing the ER-mitochondria tethering. Similarly, the co-expression of the pro-fusion protein Mitofusin 2 blocks the effects induced by p53 on mitochondria, confirming that the modulation of the ER-mitochondria contact sites is critical to mitochondria integrity. Thus, the impairment of ER-mitochondria communication, as a consequence of DJ-1 loss-of-function, may be detrimental for mitochondria-related processes and be at the basis of mitochondrial dysfunction observed in Parkinson disease.

The coming of age of the mitochondria–ER contact: a matter of thickness

“…These data indicate that the structural plasticity of the MERC cleft accompanies changes in cell metabolism, possibly as part of an adaptive process, consistent with the notion that mitochondrial ultrastructure and bioenergetics are tightly integrated to cell physiology. [27][28][29] Impairing the remodeling of the MERC thickness might, therefore, underlie the development of those pathologies that have been linked to altered MERCs activity, such as Alzheimer's disease (AD), 30 Parkinson's disease 31 and cancer.…”

The role of Ca2+ signaling in Parkinson's disease

“…These interactions promote MAM assembly and function by controlling ER-mitochondria Ca 2+ and lipid homeostasis (Table 1, Fig. 2) (Calí et al, 2012b; Guardia-Laguarta et al, 2014; Ottolini et al, 2013). These data suggest that disruption of MAMs might also be an important contributor to the pathogenesis of PD.…”

Mitochondrial control of cell bioenergetics in Parkinson’s disease

“…On the other hand, DJ-1 fosters the communication between RE and mitochondria [238], hence reducing DJ-1 levels causes mitochondrial fragmentation and decreased mitochondrial Ca 2+ uptake. In HeLa cells, overexpression of p53 impairs the transfer of Ca 2+ from ER to mitochondria increasing mitochondrial fragmentation; this was reversed by DJ-1 overexpression rescuing the ER-mitochondria contact sites, but not by Drp1 inhibition, indicating that mitochondrial fragmentation was independent of Drp1 activation [38]. Thus, besides its antioxidant role, DJ-1 participates in the maintenance of mitochondria integrity by improving ER-mitochondria communication.…”

“…ER-mitochondria contact sites transfer Ca 2+ from ER to mitochondria to sustain cell metabolism and bioenergetics [28, 37, 38]. Recent studies suggest PD to be linked to other metabolic diseases, such as diabetes or metabolic syndrome [39].…”