Human-derived neurons provide the answers: Pathways involved in energy metabolism and removal of cellular debris by lysosomes play an important role in protecting our brain from degeneration in Parkinson's disease. Burbulla et al. identified a toxic cascade of mitochondrial and lysosomal dysfunction in human neurons derived from patients with Parkinson's. The dysfunction was mediated by accumulation of oxidized dopamine and α-synuclein, but it was not found in Parkinson's mouse models, owing to species-specific differences in dopamine metabolism. Inherent species-specific differences between human and mouse neurons emphasize the value of studying human neurons to identify relevant targets for treatment of Parkinson's disease and related synucleinopathies. Science , this issue p. 1255

How do neurons match generation of adenosine triphosphate by mitochondria to the bioenergetic demands of regenerative activity? Although the subject of speculation, this coupling is still poorly understood, particularly in neurons that are tonically active. To help fill this gap, pacemaking substantia nigra dopaminergic neurons were studied using a combination of optical, electrophysiological, and molecular approaches. In these neurons, spike-activated calcium (Ca ²⁺ ) entry through Ca _v 1 channels triggered Ca ²⁺ release from the endoplasmic reticulum, which stimulated mitochondrial oxidative phosphorylation through two complementary Ca ²⁺ -dependent mechanisms: one mediated by the mitochondrial uniporter and another by the malate-aspartate shuttle. Disrupting either mechanism impaired the ability of dopaminergic neurons to sustain spike activity. While this feedforward control helps dopaminergic neurons meet the bioenergetic demands associated with sustained spiking, it is also responsible for their elevated oxidant stress and possibly to their decline with aging and disease.

Degeneration of substantia nigra (SN) dopaminergic (DAergic) neurons is responsible for the core motor deficits of Parkinson’s disease (PD). These neurons are autonomous pacemakers that have large cytosolic Ca²⁺ oscillations that have been linked to basal mitochondrial oxidant stress and turnover. This review explores the origin of Ca²⁺ oscillations and their role in the control of mitochondrial respiration, bioenergetics, and mitochondrial oxidant stress.

Parkinson’s disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP⁺). We demonstrate that the higher level of neurotoxicity in SN than VTA neurons was due to SN neuron-specific toxin-induced increase in cytosolic dopamine (DA) and Ca²⁺, followed by an elevation of mitochondrial Ca²⁺, activation of nitric oxide synthase (NOS), and mitochondrial oxidation. The increase in cytosolic Ca²⁺was not caused by MPP⁺-induced oxidative stress, but rather depended on the activity of both L-type calcium channels and aSyn expression, suggesting that these two established pathogenic factors in PD act in concert.