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The Rho GTPase Miro1, located at the mitochondrial outer membrane is known to properly distribute mitochondria to synapses, aid calcium buffering and initiate PINK1-Parkin mediated mitophagy. Several heterozygous RHOT1/Miro1 variants were identified in sporadic Parkinson’s disease patients. Miro1 R272Q is located within a calcium binding domain, but the functional outcome of this point mutation and its contribution to the development of disease are unclear. To address this, we introduced a heterozygous RHOT1/Miro1 R272Q point mutation in healthy induced pluripotent stem cells. In dopaminergic neurons, Miro1 R272Q does not affect Miro1 protein levels, CCCP-induced mitophagy, nor mitochondrial movement yet causes the fragmentation of mitochondria with reduction of cristae and ATP5A. Inhibition of the mitochondrial calcium uniporter phenocopied Miro1 R272Q cytosolic calcium response to Thapsigargin in active neurons, a similar effect was observed during the calcium buffering phase in Miro1 knockdown neuroblastoma cells. Altered mitochondrial calcium regulation is associated with reduced mitochondrial respiration and reduced catecholamine neurotransmitter uptake. Synaptic changes are not coupled to dopamine distribution or dopamine transporters but are linked to Miro1 R272Q-related calcium handling via the mitochondria concomitant with defective dopamine regulation at the mitochondrial surface by monoamine oxidase. We conclude that the Miro1 R272Q heterozygous point mutation dampens mitochondrial-calcium regulation and mitochondrial capacity via events at the outer membrane that are sufficient to disrupt dopaminergic function.

The search for treatments for neurodegenerative diseases is a major concern in light of today's aging population and an increasing burden on individuals, families, and society. Although great advances have been made in the last decades to understand the underlying genetic and biological cause of these diseases, only some symptomatic treatments are available. Metformin has long since been used to treat Type 2 Diabetes and has been shown to be beneficial in several other conditions. Metformin is well-tested in vitro and in vivo and an approved compound that targets diverse pathways including mitochondrial energy production and insulin signaling. There is growing evidence for the benefits of metformin to counteract age-related diseases such as cancer, cardiovascular disease, and neurodegenerative diseases. We will discuss evidence showing that certain neurodegenerative diseases and diabetes are explicitly linked and that metformin along with other diabetes drugs can reduce neurological symptoms in some patients and reduce disease phenotypes in animal and cell models. An interesting therapeutic factor might be how metformin is able to balance survival and death signaling in cells through pathways that are commonly associated with neurodegenerative diseases. In healthy neurons, these overarching signals keep energy metabolism, oxidative stress, and proteostasis in check, avoiding the dysfunction and neuronal death that defines neurodegenerative disease. We will discuss the biological mechanisms involved and the relevance of neuronal vulnerability and potential difficulties for future trials and development of therapies.