Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration

Abstract

Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP+) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP+ and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.

Extremely low-frequency pulses of faint magnetic field, weaker than the geomagnetic field, induce mitophagy to rejuvenate mitochondria

“…We show that Opti-ELF-WMF induced mitophagy, followed by upregulation of the mitochondrial ETC activity. Similar to our observation, chemical inhibition of mitochondrial ETC complex II potentially provides neuroprotection by inducing autophagy in cultured neuronal cells 32 . Opti-ELF-WMF may be applicable in the treatment of neurodegenerative, mitochondrial, and other diseases, in which amelioration of compromised mitophagy and enhancement of normal mitophagy would be bene cial.…”

SCD1, autophagy and cancer: implications for therapy

“…4 a). Recently, it has been noticed that the inhibition of the mitochondrial complex II through the toxin 3-nitropropionic acid (3-NPA), resulted in incomplete autophagy and lack of neuroprotection [ 93 ]. Taken together, these observations suggest that SCD1-modulated metabolites may influence the autophagic process, thus making their interconnection in cancer even more complex and intriguing.…”

Inhibition of 2-Oxoglutarate Dehydrogenase as a Chemical Model of Acute Hypobaric Hypoxia

“…Thus, translational value of the results obtained in the chemical models of pathologies essentially depends on the knowledge of molecular features of the complex pathophysiology, which are reproduced by the model, and those which characterize the substance-specific action. In particular, although mitochondrial impairment occurs upon inhibition of either complex I or II, different downstream pathways are activated by each of specific mitochondrial inhibitors, potentially reproducing the symptoms specific for particular neurodegenerative diseases (8).…”