Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake

Abstract

Mitochondrial Ca2+ homeostasis is fundamental to regulation of mitochondrial membrane potential, ATP production, and cellular Ca 2+ homeostasis. It has been known for decades that isolated mitochondria can take up Ca 2+ from the extramitochondrial solution, but the molecular identity of the Ca 2+ channels involved in this action is largely unknown. Here, we show that a fraction of canonical transient receptor potential 3 (TRPC3) channels is localized to mitochondria, a significant fraction of mitochondrial Ca 2+ uptake that relies on extramitochondrial Ca 2+ concentration is TRPC3-dependent, and the up-and down-regulation of TRPC3 expression in the cell influences the mitochondrial membrane potential. Our findings suggest that TRPC3 channels contribute to mitochondrial Ca 2+ uptake. We anticipate our observations may provide insights into the mechanisms of mitochondrial Ca 2+ uptake and advance understanding of the physiological role of TRPC3.

Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries

“…The mPT begins with the assembly of the mPTP and collapse of the inner ψm and continues with swelling and rupture of the outer membrane and the release of proteins, generation of large amounts of ROS, and death of the cell by necrosis. An important intermediary step is the massive entry of Ca 2+ into the matrix carried not only by mitochondrial Ca 2+ uniporter (MCU) but also by a fraction of TRPC3 embedded in the inner mitochondrial membrane and functioning in parallel with MCU (58). Our data show that the TRPC3 channels play roles not commonly thought of for TRPC channels, i.e., ROS synthesis at the plasma membrane as a result of steady membrane stretching and ROS synthesis by mitochondria as a result of the uncoupling of the respiratory chain associated with Ca 2+ overload.…”

Brain-derived Neurotrophic Factor (BDNF)-induced Mitochondrial Motility Arrest and Presynaptic Docking Contribute to BDNF-enhanced Synaptic Transmission

“…In our experiments, it is likely that at presynaptic sites TRPC3 forms heteromers with TRPC6 and is activated by BDNF, allowing Ca 2ϩ influx and resulting in higher intracellular Ca 2ϩ at the synaptic sites, which leads to more mitochondrial docking at synaptic sites regardless of anterograde or retrograde movement of mitochondria. Interestingly, Feng et al (43) recently reported that TRPC3 localizes not only to plasma membrane but also to the inner mitochondrial membrane and that it contributes to mitochondrial Ca 2ϩ uptake. One study has suggested mitochondrial matrix Ca 2ϩ content to be an intrinsic signal for modulating mitochondrial motility in neurons (44).…”

The Actin-Related Protein2/3 Complex Regulates Mitochondrial-Associated Calcium Signaling during Salt Stress inArabidopsis

“…Changes in [Ca 2+ ] cyt are perceived and transduced by these proteins to signal downstream responses. However, it has been unclear whether external Ca 2+ stores (the apoplast) or internal stores (such as the endoplasmic reticulum, Golgi bodies, the vacuole, or mitochondria) are responsible for the [Ca 2+ ] cyt changes and how these stores are regulated during salt stress (Feng et al, 2013). Our results demonstrate that the salt-induced increase in [Ca 2+ ] cyt in arp2-2 results partly from mitochondrial Ca 2+ stores.…”