Parkinson’s disease is, at the neuropathological level, characterized by the death of dopaminergic neurons. PD pathogenesis is multifactorial, there are several mechanisms that malfunction leading to the death of dopaminergic neurons. The mitochondria are vital for the normal functioning of a cell, they are the primary energy generator for the cell. In addition to their energy metabolism role, mitochondria are involved in many cellular processes, such as the stress response and cell death pathways. As a result, mitochondrial impairment and the genes that are related to its functionality are linked to progressive neurodegeneration. Considering parkin, PINK1, DJ-1, and LRRK2 gives insight into how PD develops and potential therapeutic options. Mitochondrial dysfunction works in conjugation with another classic PD characteristic, the accumulation of misfolded proteins. ER stressed caused by the accumulation and formation of aggregates induces a cellular defense mechanism, UPR; however, chronic ER stress impairs many of the protective functions that the cell possesses leading to cell death. Individually mitochondrial dysfunction and ER stress have been implicated in PD, but their interaction is not entirely understood. Furthermore, the role of key mitochondrial related PD genes in mitochondria-ER stress resulting in dopaminergic neurodegeneration has not been fully integrated in literature. This review attempts to reconcile these key mechanistic events.